THE H U M A N BREAST AND THE ANCESTRAL REPRODUCTIVE CYCLE A Preliminary Inquiry into Breast Cancer Etiology
K a t h r y n Coe
Lyle B. S t e a d m a n
Hispanic Research Center Arizona State University
Department of Anthropology Arizona State University
This paper, u s i n g m o d e r n D a r w i n i a n theory, proposes an e x p l a n a t i o n for the i n c r e a s i n g l y high incidence of breast cancer f o u n d a m o n g preand p o s t - m e n o p a u s a l w o m e n l i v i n g today in w e s t e r n i z e d countries. A n u m b e r of factors have b e e n said to be responsible: genetic inheritance (BRCA-1), diet (specifically the increased c o n s u m p t i o n of dietary fat), exposure to carcinogenic agents, lifetime m e n s t r u a l activity, and reproductive factors. The p r i m a r y aim of this p a p e r is to demonstrate the value of a perspective based on D a r w i n i a n theory. In this paper, D a r w i n i a n theory is used to explore the p o s s i b i l i t y that the increased incidence of breast cancer is due p r i m a r i l y to the failure to complete in a timely m a n n e r the reproductive d e v e l o p m e n t a l cycle, b e g i n n i n g at menarche and c o n t i n u i n g t h r o u g h a series of pregnancies a n d lactation. O n the basis of comparative data, we a s s u m e that most w o m e n in ancestral p o p u l a t i o n s b e g a n h a v i n g c h i l d r e n before age 20 or so and t e n d e d to r e m a i n either p r e g n a n t or n u r s i n g for most of their adult lives. If a w o m a n did n o t have a child b y age 25 or so, she p r o b a b l y w o u l d n e v e r have one. Therefore, selection w o u l d p r o b a b l y not have acted against deleterious traits, such as cancer, that appeared after that age, just as it does not act against such traits in old age.
Received October 27, 1994; accepted January 23, 1995.
Address all correspondence to Kathryn Coe, Hispanic Research Center, Arizona State University, Tempe, AZ 85287-2702 Copyright 9 1995 by Walter de Gruyter, Inc. New York Human Nature, Vol. 6, No. 3, pp. 197-220. 197
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KEY WORDS: Breast cancer; Breast development; Darwinian theory; Human reproductive cycle.
Breast cancer is referred to as a disease of modern civilization, by which is meant that women living today in developed countries, or living a westernized lifestyle in developing countries, experience higher risk for this disease than do women living in tribal societies or third world countries (Learmonth 1988). Eaton et al. (1994) suggest that the risk of women living in industrialized societies may be as much as 100 times that of pre-agricultural women. This increased incidence has been said to be correlated with such things as diets that are increasingly high in saturated fat, contact with carcinogenic agents, hormonal events associated with menstrual activity or anovulatory menstrual cycles, a n d / o r reproductive factors. Findings, unfortunately, are confusing and contradictory, often because studies fail to focus on or examine the same variables (Rautalahti et al. 1993; I. Russo and J. Russo 1993). In this paper, Darwinian theory is used to formulate a hypothesis focusing on differences between the present environment and that of our evolutionary past. This hypothesis proposes that increased breast cancer risk is related to recent changes in the reproductive developmental sequence that is initiated at puberty and involves a series of pregnancies and lactation. To begin this discussion we need a definition and some relevant facts.
WHAT IS CANCER? Cancer begins when a single normal cell experiences particular kinds of genetic changes, called mutations, which result in loss of normal controls over key cellular processes, thus converting a normal cell into one whose descendants will all become cancer cells (Prescott and Flexer 1982). Cancer cells, unlike normal cells, grow and divide rapidly and irregularly; have an unstructured appearance; show abnormalities in the structure of DNA molecules; have the ability to invade adjacent, normal tissue; have greatly prolonged life spans; and do not perform normal functions in the body (Prescott and Flexer 1982). Cancer cells draw on the body's nutrient supplies but contribute nothing to the functioning of the body (Learmonth 1988). As cancer cells grow, neoplasms, or tumors, are formed. Breast cancer is a heterogeneous disease, the most common histological type of which is infiltrating ductal carcinoma (Russo and Russo
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1992), which appears to involve a continuum of histologic changes in the ducts of the breast. Such changes begin with ductal hyperplasia, which can progress to atypical hyperplasia, then to ductal carcinoma in situ, and finally to invasive carcinoma (Strah and Love 1992). Ductal carcinoma in situ (DCIS), referred to as a precancer, is characterized by malignant epithelial cells that fill the m a m m a r y ducts without disruption or involvement of the basement membrane; unlike invasive cancer, DCIS lacks the ability to invade or metastasize (Strah and Love 1992).
INCIDENCE Breast cancer is primarily a disease of human females; in males this disease is quite rare (Swanson 1992). Breast cancer is one of the most frequently diagnosed malignancies and is now the second leading cause of cancer mortality among westernized women. Incidence is high in Canada and the United States. Within the United States, average annual incidence in 1977-1983 was highest among Native Hawaiian women, whose rate was about 10% higher than among white women: 106.1 per 100,000 women, compared with an incidence in white women of 96.8. Incidence during this same period was lowest among Native American (21.3 per 100,000), Alaskan native (44.2), and Hispanic (52.1) women (Swanson 1992). In Europe, incidence is highest in France, Sweden, Denmark, Switzerland, the United Kingdom, and the Netherlands and lowest in Spain, Hungary, Romania, Poland, and Czechoslovakia (Baanders and de Waard 1992). During the period 1978-1982, the age-standardized rates in Europe ranged from 71.6 (per 100,000) in the Netherlands to 27.2 in Hungary. Incidence is low in India, Philippines, Kuwait, and in most Asian, African, and South American countries (Baanders and de Waard 1992; Kelsey 1979; Swanson 1992). Incidence of breast cancer in westernized countries appears to have increased significantly during the past few decades (Baanders and de Waard 1992) and may be reaching epidemic proportions (Marshall 1993; Nesse and Williams 1994; J. Russo and I. Russo 1993). In 1937, shortly after formal registration of this tumor was initiated, 58 per 100,000 women were diagnosed with breast cancer. In 1973, this number had increased to 83.9, and in 1988, to 112.9 (Swanson 1992). Although some of the increased incidence can be explained as screening effect, this source of bias cannot explain the long-term increase in breast cancer incidence because screening was not widespread until the mid 1980s (Colditz 1993). Further, screening effect cannot explain w h y breast cancer appears to be affecting younger women who are not regularly screened (Howe et al. 1989; Mayberry and Stoddard-Wright 1992).
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One recent study found that the risk of breast cancer increases among premenopausal women by about 11% each year until menopause, after which age becomes irrelevant (Rautalahti et al. 1993). Another study conducted in Washington found that for women aged 25--44 years, the incidence of breast cancer increased by 22% between 1974-1977 and 1982-1984, with an estimated annual increase of 2.5% (p < 0.001) (White et al. 1987). During these same periods, breast cancer incidence declined 12% for women age 45-54 years and 9% for women age 55 years and olden
RISK FACTORS Breast Cancer Is an Inherited Disease
One accepted risk factor of breast cancer is a family history of the disease (Anderson and Badzioch 1985; Bowcock et al. 1993; Kelsell et al. 1993; Kelsey 1979). Family history correlations m a y imply that similar environmental or social factors are operating (e.g., shared dietary habits produce similar endocrine or anthropometric features) (Kato et al. 1992; Swanson 1992); however, they also m a y imply genetic involvement. Although inheritance of BRCA-1, a marker found in the region between DNA markers D17S193 and D17S857 (Bowcock et al. 1993; Kelsell et al. 1993; Swanson 1992), does significantly increase one's chances of getting cancer (their lifetime risk may approach certainty) (Bishop 1993), inheritance explains only a small percentage of breast cancer cases, possibly less than 2% (Swanson 1992). 1
Breast Cancer and Contact with Environmental Toxins and Carcinogens
Carcinogens are agents that cause a statistically significant increase in the incidence of neoplasms when administered to individuals in a population of previously untreated organisms. These agents can be physical; biological, such as viruses; or chemical, such as complex hydrocarbons, aromatic amines, certain metals, chemicals that occur naturally in molds and plants, and hormones (Prescott and Flexer 1982; Rosenberg and Berry 1992; Russo et al. 1982). Chemical carcinogens appear to alter the DNA of the normal cell, thus modifying the content or flow of genetic information coded in the DNA's base sequence. Reactive electrophilic
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intermediates or carbonium ions appear to be formed during the metabolism of carcinogens. It is the reaction of these highly reactive intermediates with cellular components that may initiate the chain of events that results in cancer (Russo et al. 1982). The ultimate carcinogenicity of any compound seems to depend upon two factors: level of metabolites in target tissue available for interaction with critical cellular nucleophiles and presence of susceptible or nonsusceptible tissues (Russo et al. 1982). Susceptibility of the cell to undergo malignant transformation seems to be correlated with the rate of DNA synthesis and cell proliferation, and cellular competency in DNA excision repair (Russo et al. 1982). Developmental stages involving cell proliferation may be crucial, as cell proliferation is the driving force of tumor growth; carcinogens induce a greater response in dividing than in resting cells (Eaton et al. 1988; Russo and Russo 1988). Hormones, endogenous and exogenous, have been implicated in breast cancer because the development of many tumors appears to be hormone dependent; tumor growth can be suppressed by hormone deprivation, hormone administration, or pregnancy and lactation (Russo et al. 1990). Experimental studies using animals have shown that hormones can have a profound influence on breast tumor development; when human breast cancer cells are transplanted into mice, supplemental hormones must be administered if progressive epithelial tumor growth is to be sustained (Soule and McGrath 1980). Estrogens, which are ovarian hormones, have been implicated in breast cancer based on the assumption that their function is to initiate cell proliferation, whereas the function of progesterone is to inhibit estrogen receptors in the uterus, pituitary gland, and hypothalamus, and thus inhibit cell proliferation. However, recent studies have also implicated early high doses of progesterone in increasing breast cancer risk. In rats, a high dose of the estrogenic agent norethynodrel-mestranol was protective against the formation of tumors, while a similar dose of medroxprogesterone acetate increased tumor incidence (Russo and Russo 1988). At this point it is unclear whether estrogen or progesterone plays the stronger role in tumorigenesis, nor is it clear whether the role they play is an initiating one, a promoting one, or a growth-enhancing one. Recent studies of the sequence in which the particular hormones reach their target suggest that if they reach cells already affected b y a carcinogen, the hormones will act as promoters of tumorigenesis. If, on the other hand, hormones reach normal cells, they will induce differentiation of the breast (as explained later in this paper), thus eliminating the possible targets of carcinogens and abolishing the gland's potential for neoplastic transformation (Russo and Russo 1988).
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Breast Cancer and a Diet High in Saturated Fats
Circumstantial evidence for the etiologic role of dietary fat is found in immigration studies and studies of changes through time in diet. The increase in breast cancer found among offspring of Japanese emigrants to the United States can be correlated with subsequent changes in dietary habits (Kelsey 1979; Swanson 1992). When we examine the diet of the Bantu of South Africa, who consume approximately 15% of their calories from fat, the breast cancer mortality rate is 5 per 100,000 women, whereas among African-American women living in the United States, who consume a diet with 40% of the calories derived from fat, the breast cancer death rate is 23 per 100,000 (Swanson 1992). Further, the slow but steady increase in breast cancer incidence in the United States has been accompanied by a steady increase in dietary fat consumption (Kelsey 1979). Experimental studies using rats have shown that diets that are high in fat promote the development of both spontaneous and chemically induced breast cancer (Carroll and Khor 1971; Chan and Cohen 1974; Eaton et al. 1988; Tannenbaum 1942). This risk holds true at all ages (Swanson 1992). Although these studies indicate a correlation between fat consumption and breast neoplasms (Carroll et al. 1968), other studies, including a cohort study of 90,000 nurses, found no relationship between breast cancer and meta intake, calorie-adjusted total fat intake, or saturated fat intake and concluded that modification of dietary fat intake among adults was unlikely to reduce breast cancer risk (Colditz 1993; Willett et al. 1987). A recent meta-analysis concluded that high fat intake only has a modest effect on breast cancer risk (Howe et al. 1990). Such studies have led some major researchers to conclude that evidence supporting the fat-intake hypothesis just does not exist (Marshall 1993). One problem in the study of dietary fat is the fact that the mechanism by which dietary fat, or even stored body fat, increases breast cancer risk is unclear. High dietary fat consumption may exert an independent effect on breast cancer risk or it may act primarily through an influence on hormonal status (Swanson 1992). Dietary fat consumption appears to affect enteric reabsorption of steroid hormones by influencing the intestinal flora (Mansfield 1993). Obesity and body fat distribution also seem to increase estrogen levels (Swanson 1992). The breast tissue of obese women may be exposed to higher levels of estrogens owing to a lower production of 2-OH estrogen compounds; this may lead to a relative hyperestrogenic state (Tabar et al. 1985). An additional problem with dietary fat studies is that it is not clear if the effect of fats might be greater
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at the promotional stage of cancer or at the initiation of carcinogenesis (Kelsey 1979; Spiro 1993). Further, the relationship between variables such as age and dietary fat consumption typically have not been evaluated. Dietary fat may, for example, increase risk only if consumed in large amounts at particular ages. If dietary fat is related to increased breast cancer incidence via its influence on sex hormones, it is possible that fat consumption is critical at prepuberty and early puberty (Swanson 1992).
Breast Cancer and Lifetime Menstrual Activity In a number of studies, early menarche has been shown to increase risk for breast cancer. The age at menarche in the United States is estimated to have decreased by four months per decade during the period from 1840 to 1960 (Colditz 1993). Women in the United States and other industrialized societies tend to enter menarche two to three years earlier than women in countries like China (Wang et al. 1992). In China, w o m e n with their first menstrual period at age 12 years or earlier had an approximately 80% higher breast cancer risk than women who started menstruating at age 17 or later (Wang et al. 1992). In Tokyo, w o m e n who began to menstruate at age 13 years or younger had twice the breast cancer risk of women with menarche occurring after age 16 (Yuasa and MacMahon 1970). Age at menarche may be less important in determining breast cancer risk than the period of time elapsed between the onset of menarche and the birth of the first child. Baanders and de Waard argue that "almost 60% of the variance in breast cancer incidence in Europe can be explained by the length of the interval between menarche onset and the birth of the first child" (1992:289). Another study conducted in the United Kingdom found that intervals between menarche and first birth longer than 14 years significantly increased breast cancer risk in women over 61 (De Stavola et al. 1993). Early natural menopause has been said to confer a protective effect against breast cancer (Colditz 1993; Spiro 1993). Breast cancer patients have shown a higher mean age at natural menopause than women without breast cancer (Mansfield 1993). In Tokyo, women reporting menopause at age 50 years or older had a slightly higher risk of breast cancer than did women reporting menopause prior to age 50 (Yuasa and MacMahon 1970). In a study conducted in Burma, the trend toward increasing risk of breast cancer with increasing age at menopause was highly significant (p = 0.00003) (Thein-Hlaing and Thein-Maung-Myint 1978). Since increased risk for breast cancer appears to be correlated with both early menarche and late menopause, researchers began to focus on
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menstrual activity over the lifetime. One can estimate lifetime d u r a t i o n of m e n s t r u a l activity b y taking the years from m e n a r c h e to m e n o p a u s e and subtracting periods spent p r e g n a n t or lactating (Eaton et al. 1994; Nesse and Williams 1994; Rautalahti et al. 1993). It is not clear at w h a t point, or after h o w m a n y m e n s t r u a l cycles, a w o m a n ' s risk m a y increase. Some h a v e argued that risk m a y increase o n l y after a n u m b e r of years, perhaps after 30 years of m e n s t r u a l activity (Najem et aL 1982).
Breast Cancer and Full-Term Pregnancy Although some studies have indicated that parity has n o effect on breast cancer risk (Najem et al. 1982; Stavrakey a n d E m m o n s 1974; Talamini et al. 1985), others seem to lend strong s u p p o r t to the h y p o t h esis that parous w o m e n are at l o w e r risk for breast cancer than nonparous w o m e n ( H o w e et al. 1989). Since the 1970s, the inverse relationship b e t w e e n parity and breast cancer risk has been seen as principally a reduction in risk associated with early age at first birth. A striking reduction of breast cancer risk associated with h a v i n g a full-term pregnancy early in reproductive life was o b s e r v e d in data from a casecontrol s t u d y of 4,000 breast cancer cases and 12,000 controls from seven areas of the w o r l d (MacMahon et al. 1970). In a n u m b e r of other studies, first p r e g n a n c y before age 18 (Russo et al. 1982) or age 20 (Kelsey 1979; M a c M a h o n et al. 1970; S w a n s o n 1992; Thein-Hlaing and Thein-Maung-Myint 1978; Wang et al. 1992) was related to breast cancer risk. This r e d u c e d risk m a y be greater in prem e n o p a u s a l w o m e n (Kampert et al. 1988). First p r e g n a n c y at age 30 years or thereafter significantly increased risk (to 3.2 times the risk of w o m e n w h o s e first birth was before age 20) ( M a y b e r r y and S t o d d a r d Wright 1992; Salber et al. 1969; Thein-Hlaing and T h e i n - M a u n g - M y i n t 1978; Wang et al. 1992). W o m e n w h o s e first birth occurs at 30-34 years m a y have approximately the same risk as nulliparous w o m e n , and w o m e n w h o s e first birth is at age 35 or later m a y h a v e higher risk than nulliparous w o m e n (Mansfield 1993; M a c M a h o n et al. 1970). The early first p r e g n a n c y m u s t be full term if cancer risk is to be reduced. Pike et al. (1981) f o u n d a 2.4-fold increase in risk for breast cancer associated with first trimester abortion (spontaneous or i n d u c e d ) before the first term p r e g n a n c y (see also M a c M a h o n et al. 1982). Although findings are contradictory (see A n d r i e u et al. 1993; H o w e et al. 1989), a n u m b e r of studies do s u p p o r t that the risk of breast cancer increases significantly w h e n w o m e n experience an abortion prior to a first live birth (Brinton et al. 1983; Hadijimichael et al. 1986; H o w e et al. 1989; Lindefors-Harris et al. 1989; Parazzini et al. 1991; Pike et al. 1981).
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In Washington the breast cancer rate among poor w o m e n rose by 53% in the period 1974-1984, after the state started funding abortions (Cates 1982; Krieger 1990). Daling et al. (1994) suggest that the risk of breast cancer may be especially high if the female is younger than 18 and her abortion occurred after 8 weeks of gestation, or if the w o m a n was age 30 or olden Although many researchers claim, along with Baanders and de Waard (1992), that age at first birth is the most important, hormone-associated, risk-factor of breast cancer, recent studies point out that a pregnancy may initially boost the level of risk (Colditz 1993; Kampert et al. 1988; Lambe et al. 1994; Pike et al. 1983). Lambe et al. (1994) have proposed that pregnancy has a dual effect on breast cancer risk: increasing shortterm risk while conferring long-term protection.
Breast Cancer and Lactation
For centuries the claim has been made that the breast that never was used for nursing was more liable to become cancerous (see Doll 1975); however, evidence regarding this claim has been contradictory. In 1960s and 1970s, MacMahon and his associates found no important association between lactation and risk of breast cancer in data from a series of international case studies. Controlling studies for age of first pregnancy, they argued, caused any association to disappear. They concluded that the reported relationship between lactation and breast cancer could be explained by other intermediate variables, such as age, parity, and socioeconomic status (MacMahon and Feinleib 1960; MacMahon et al. 1973). Consequently, lactation generally was not regarded as an independent risk factor in studies of breast cancer (London et al. 1990). Recently, however, several researchers have reported that lactation m ay be associated with decreased risk of breast cancer (Byers et al. 1985; Kelsey and John 1994; Lubin et al. 1982). Wang et al. (1992) found that w o m e n in China w ho accumulated at least nine years of breast feeding had about one-sixth the risk of w om en who never nursed and one-half the risk of wo me n whose nursing time was three years or less. Risk decreased about 11% for each year of lactation experience, and this trend of decreasing risk with increasing months of lactation was highly significant (p for linear trend = 0.00003). McTiernan and Thomas (1986) have also claimed that there is a definite association between a longer experience of lactation and decreased risk of breast cancer, particularly in premenopausal women. And even MacMahon now supports the suggestion that there is a reduction in breast cancer among premenopausal w o men who have lactated (Newcomb et al. 1994).
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Cancer and Number of Full-Term Pregnancies Most researchers agree that breast cancer risk, after age 45, decreases with increasing parity (Kelsey and John 1994; Salber et al. 1969). In studies from Burma, Iceland, Sweden, and Buffalo, New York, high parity appears to offer additional protection beyond that offered by early age at first birth (Kalache et al. 1993; MacMahon et al. 1982). In Brazil (509 cases, 509 controls), increasing parity was strongly associated with decreasing cancer risk (p < 0.001) (Kalache et al. 1993). In China (300 cases, 300 controls), women with five or more full-term pregnancies had one-tenth the risk of women with just one full-term birth (Wang et al. 1992). This risk, which decreased with increments in full-term pregnancies (p for linear trend < 0.00005), decreased 22% with each full-term pregnancy (Wang et al. 1992). In Burma (193 cases, 400 controls), women who had six or more children had only one-third the risk of women with less than four children (Thein-Hlaing and Thein-Maung-Myint 1978). A study conducted in Estonia (322 cases, 694 controls) found that a second birth before the age of 25 was associated with a substantial and statistically significant reduction in risk, to one-third of the risk for a uniparous w o m a n who did not have a second child before that age (MacMahon et al. 1982). The risk for women having two births or more under the age of 25 years, after adjustment for age at first birth, was estimated to be 13% lower than for women who had only one birth under that age. Not only were subsequent births associated with additional protection against breast and also ovarian cancer, but the extent of protection depended on the subject's age at the time of the birth (MacMahon et al. 1982; Mori et al. 1988). There is some evidence of a synergistic effect of parity and age, suggesting that having a few children at a young age (before 30-33) can be protective (Remennick 1989). The low incidence of breast cancer in eastern European countries such as Estonia, which have low fertility, may be explained by early age at first birth. In Czechoslovakia, age at first birth is 22.39; in Hungary, 22.40; in Poland, 22.80; in Yugoslavia, 22.76; and in Romania, 22.30. These ages are contrasted with those in countries of high incidence. In Ireland the average age at first birth is 26.08, in the Netherlands it is 25.74, and in England and Wales it is 24.96 (Baanders and de Waard 1992).
A DARWINIAN HYPOTHESIS Although a coherent theory of breast cancer has yet to emerge, a number of interesting correlations have been pointed out, the strongest of which may be that between menstruation and breast cancer. In 1973,
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MacMahon et al. showed that the incidence of breast cancer is strongly correlated with the number of menstrual cycles experienced by w o m e n prior to their first birth. Unopposed estrogen, which is released during the menstrual cycle, seems to be the main carcinogenic agent. In 1976, Short argued that the high frequency of menstrual cycles experienced by women in industrialized societies is a deviation from the h u m a n ancestral strategy. Short argued that in recent hunter-gatherer (and, by extension, ancestral) societies, females began menarche later and had their first child at about age 19 or so, nursed for several years, and continued bearing children and nursing until menopause. Eaton et al. (1994) have recently developed Short's evolutionary perspective further to explain the increased incidence of h u m a n female reproductive cancers, including breast cancer. According to the evolutionary approach, an understanding of humans living today requires an understanding of the environment in which humans evolved, since all organisms are products of natural selection acting on traits in ancestral populations. If we assume that the life of women in tribal societies more closely resembles that of our distant ancestresses than does our present lifestyle, we can use comparative data from these societies to reconstruct the way in which our ancestresses most likely lived. To the extent to which the modern environment and behavior deviate from that past, problems in modern populations may be a consequence of such deviation (see Eaton et al. 1994; Nesse and Williams 1994; Williams and Nesse 1991). Given high infant mortality, in the past females optimized the number of their offspring to maximize the number of their descendants by being pregnant or nursing almost continuously between menarche and menopause. This strategy presumably included mechanisms that were selected to resist anything that would impede it. The reproductive strategy of ancestral females, involving a particular timed sequence beginning at menarche and continuing through a series of pregnancies and lactation, must have differed significantly from patterns found today. Today, it is not unusual for women to postpone first reproduction, at times into their late thirties, and to have only a few offspring, w h o m they may fail to nurse. Based on comparative ethnographic data, w o m e n in ancestral populations married young, near puberty, and began having children every few years until menopause. 2 Thus, an ancestral female who failed to have a child by age 25 or so probably would never have one; she most likely would be barren forever. Furthermore, if menopause is the result of natural selection and was, as some have suggested (e.g., Alexander 1976), designed to help a female maximize the number of her descendants by directing her care toward existing children rather than continuing to have children up to
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her death, there should be some selection against deleterious traits, such as cancer, even after menopause. Not until a female who has had a number of offspring approached her likely age at death would selection cease to operate against deleterious traits. However, because a female who has not had offspring by age 25 or so is unlikely ever to have offspring, selection would not necessarily work to strengthen her ability to resist deleterious traits. On the other hand, selection should continue to operate on a male up to his death, regardless of his reproductive history. Thus, deleterious traits, such as cancer, are likely to be selected against only up to the age when a female or male could no longer influence her/his reproductive possibilities (Medawar 1957). We propose that the key to understanding the increased breast cancer incidence in premenopausal women is failure to complete in a timely fashion their reproductive sequence, which begins at menarche and continues through a series of pregnancies and lactation until menopause. Daly and Wilson (1978) describe in detail how, from the zygote onwards, each developmental stage depends precisely on a prior stage. In addition, the duration of each stage may be crucial; natural selection seems to have favored not only a strict, but a timed, developmental sequence. Natural selection has operated on the release of hormones, including both progesterone and estrogen, to prepare a female for repeated pregnancies and lactation. These hormones should not be pathological when released in the timed, developmental sequence of our ancestresses. However, the correlation observed between breast cancer and menstruation may be consistent with this evolutionary perspective. Based on observations made in modern tribal societies, the assumption made here is that ancestral females seldom menstruated since they almost always were either pregnant or lactating. If, as some anthropologists have observed (Malinowski 1962), women often fail to become pregnant for a period of several years after they begin menstruating (see also Short 1976), one would expect to find evolved mechanisms to protect them during this period when all reproduction lies in the future. In summary, some additions can be made to Eaton et al.'s detailed and well-presented discussion (1994) that breast cancer risk is related to lifetime menstrual activity. First, by concentrating on menstruation we may fail to appreciate the complex changes occurring in the breast that make the breast resistant to the action of carcinogens, including hormones. Second, a focus on menstruation m a y not help us understand the significantly increased risk experienced by w o m e n whose pregnancy is terminated by an induced abortion. If any pregnancy decreases risk, then even a partial pregnancy should also decrease risk. Third, because a w o m a n should not be favored to resist any deleterious traits after being nulliparous through age 25 or so, she m a y lack
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resistance to a number of such traits, including other cancers. Finally, by focusing on menstruation, a likely association between breast cancer and the very early development and the persistence of the protruding human breast, unique among primates, is ignored. The following discussions, which begin with a description of breast development, will discuss these points.
BREAST DEVELOPMENT
Although breast development begins during the embryonic period, when the nipple epithelium develops, the m a m m a r y gland is not fully developed at birth. At puberty, changes in the breast are initiated under the influence of ovarian estrogens; the enlargement of the breast is the first external sign of impending puberty in girls (Short and Drife 1977). Although the breast achieves its adult size before menarche, it achieves full development and differentiation only after a pregnancy has occurred (Russo and Russo 1987). The breasts of either nulliparous or immature (premenarcheal) females are structurally undifferentiated; the most common structure (50%) in their breasts is the virginal lobule, or lobule type one. Type two lobules, which have a more complex morphology, evolve from type one lobules within one or two years after onset of the first menstrual period. During pregnancy, type three lobules evolve out of type two lobules. A fourth type of lobule (lobule type four), which appears during lactation, is considered to be the maximal expression of breast development and differentiation and the stage at which breast development is completed. According to Russo et al. (1992), the breast of nulliparous w o m e n is composed predominantly of type one lobules, whereas the breasts of parous w o m e n contain a high percentage of lobule type three. With the end of pregnancy, the cessation of lactation, and the process of aging, type three lobules regress to type one lobules. However, in the breasts of parous women, type one lobules exhibit lower proliferative activity than they do in the breasts of nulliparous women. The protective effect of pregnancy is through its effect on gland differentiation. In rats, the more differentiated the structures of the breast at the time of carcinogen (i.e., 7,12-dimethylbenz[a]anthracene, DMBA) administration, the more benign and organized is the lesion that develops (Russo et al. 1982). In humans, the site of origin for preneoplastic lesions such as atypical ductal hyperplasias, which may evolve through a series of changes to invasive carcinoma, is the terminal ductal lobular unit, which is equivalent to lobule type one. Type two lobules might originate atypical lobular hyperplasia and lobular carcinoma in situ.
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Type three lobules might be the site of origin for nonmalignant tumors such as fibroadenomas. These findings suggests that the degree of differentiation or lobular development of the breast influences the type of tumor developed (Russo et al. 1992). Differentiation of the breast may play a key role in carcinogenesis by affecting processes that are initiated at menarche, namely the high cell proliferative activity observed in the terminal end bud. During pregnancy, breast cells are shifted from the proliferating to the resting stage, the carcinogen-DNA binding is significantly reduced, the DNA repair is more efficient, and the cells produce less-polar metabolites. These biological parameters all influence the susceptibility of the m a m m a r y gland to carcinogenesis. Full differentiation of the gland induced by pregnancy may eliminate the targets of the carcinogen, and this protective effect is maintained after the termination of pregnancy (Russo et al. 1992). Multiparity serves to extend lobular development and decrease the density of terminal end buds. After administration of the carcinogenic agent DMBA, young virgin rats experience the highest incidence of tumors while multiparous rats experience the lowest incidence. In young virgin rats, 100% of tumors are adenocarcinomas; in old virgin rats, 63% of tumors are carcinomas; and in multiparous rats, 21% of tumors are carcinomas (Russo et al. 1982). This finding suggests that complete development and differentiation of the breast may require more than one full-term pregnancy. Early pregnancy may be crucial. Cell replication in the terminal ducts of the human breast has its highest peak during early adulthood; a history of parity between the ages of 14 and 20 may be related to a "significant increase" in the number of type three lobules (Russo et al. 1992). It is during this period of rapid cell growth that the breast is most susceptible to carcinogens (Russo et al. 1982). As one example, exposure of the breasts to radiation when a female is 10 to 19 years of age is associated with especially high risk, particularly if exposure occurs around menarche (Kelsey 1979). Since early pregnancy promotes gland differentiation early in life, it shortens the amount of time proliferating breast cells are vulnerable to carcinogenic stimulus (Russo and Russo 1991). The sequence of exposure to a carcinogen and the periods of high mitotic activity may help explain w h y parity may both increase and decrease risk. As one example, type two lobules evolve several years after puberty. If a young female who primarily has only type one Iobules gets pregnant, these lobules will not evolve into type three lobules, which only evolve from type two lobules. Such females may be at high risk for cancers related to exposure to pregnancy hormones, such as progesterone. In another example, pregnancy may increase the shortterm risk of breast cancer by promoting the proliferation of cells that
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have already undergone the early stages of malignant transformation (Lambe et al. 1994). However, pregnancy also may confer long-term protection against breast cancer by inducing breast differentiation. Since each pregnancy leads to an increase in the number of type three lobules, repeated pregnancies should provide significant protection against breast cancer.
INDUCED ABORTION
Menstrual factors do not appear to be able to account for significant increases in cancer risk that may be associated with an induced abortion (Brinton et al. 1983; Cates 1982; Daling et al. 1994; Hadijimichael et al. 1986; Howe et al. 1989; Krieger 1990; Lindefors-Harris et al. 1989; Olsson et al. 1991; Parazzini et al. 1991; Pike et al. 1981; White et al. 1994). If these studies hold true, induced abortion m a y increase cancer risk even in females who have experienced very few menstrual periods. Disrupted pregnancy abruptly halts the process of breast cell proliferation. This action, described by some authors as "hormonal blow," has a strong effect on the immune, nervous, and other systems (Remennick 1989). Although cell proliferation has been initiated, the process does not promote or culminate in complete differentiation of the breast, or eliminate targets of carcinogens (Russo and Russo 1980). In rat studies, the mammary glands of animals in which pregnancy was disrupted contain some areas with completely differentiated structures and other areas in which undifferentiated structures prevail (Russo et al. 1982). These animals had the same tumor response as did virgin animals to subsequent administration of DMBA. Russo and Russo (1980) hypothesize that incomplete differentiation of the cells of the m a m m a r y gland during the first trimester increases the subsequent susceptibility of breast tissue to carcinogenic agents.
SENESCENCE Senescence involves the shutdown or impairment of body systems, making organisms more susceptible to diseases such as cancer. Senescence typically begins late in life when organisms have completed reproduction; thus it would not be unexpected in postmenopausal women. Something much like senescence, however, also may occur in females who do not follow the timed developmental sequence. Like the appearance of deleterious traits when an organism approaches its physical death, such traits expressed in an individual who will never have offspring, perhaps
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beginning as early as age 25 in ancestral h u m a n females, would not have been selected against. In ancestral populations, prolongation of the stage of development between menarche and first full-term birth, for example, also would have led to few descendants. Genes coding for cell proliferation, valuable at the time of development, could be deleterious in nonreproductive females. Failure to suppress the rapid cell growth that marks the period between menarche and first full-term pregnancy would not be selected against in barren females, just as deleterious genes that have their effect near physical senescence are not selected against. Although no studies identified in the literature have addressed subsequent cancers or other diseases in premenopausal women diagnosed with cancer in one breast, it is known that women with cancer in one breast have four to five times the risk as comparable women of the same age of developing a second primary cancer in the other breast (Kelsey 1979). Also, younger women (age less than 40 years) who develop primary breast cancer are more likely to develop a second cancer than women who developed cancer at an older age, and they are slightly more likely to die of cancer (Swanson 1992). There is a twofold increase in risk of a second primary cancer in the ovaries, following breast cancer (Kelsey 1979). Multiple primary cancers involving the breast, endometrium, and ovary share important epidemiological characteristics and occur more frequently than one would expect by chance (Kelsey et al. 1981). Also, although the evidence is both unclear and contradictory, associations have been reported between breast cancer and subsequent soft tissue sarcoma, meningioma, malignant melanoma of the eye, acute myeloid leukemia, major salivary gland tumors, and cancers of the buccal cavity, pharynx, and thyroid (Kelsey 1979).
THE HUMAN BREAST
The final point, surely relevant to this entire discussion, was raised by Short and Drife in 1977: Why does the human breast, in contrast to that of all other primates, become fully anatomically developed at puberty, well in advance of the first ovulation or the first pregnancy? And w h y does the human breast, in contrast to that of all other primates, remain protruding throughout much of the remainder of her life? Clearly, as Short recognized, this is not explained by lactation. Short and Drife (as well as most others) assume that this early breast development is erotic, aimed at arousing males sexually. However, among the Hewa of the Highlands of Papua New Guinea, a society in which women are bare breasted, breasts are referred to as "milks"; they are not involved in sexual foreplay, and people of both sexes are bewildered when asked about
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breasts being erotic. The size and shape of breasts are symbolized by both males and females by placing their hands on their chest to identify the three most important stages of a woman's life: fists indicate her prereproductive phase, hands straight out indicate that she is in her reproductive phase, and hands down indicate her post-reproductive phase. What we are proposing is that breasts did not and do not remain protruding throughout much of an ancestral female or modern woman's life because they are sexually provocative; rather their existence and attitude indicate to a possible mate the female's reproductive potential, in the same way as her age, agility, health, and symmetrical appearance. That is, breasts communicate wife potential, not temporary sexual potential. When a male marries a female with full and upright breasts he can benefit from her entire reproductive output. As her breasts decline, they signal her declining reproductive potential, and hence her declining attractiveness as a wife. In a polygynous society, a female with upright breasts can choose to marry almost anyone she wants. Keep in mind that in a polygynous society all males are more or less continuously wife-seeking, and every wife gained increases a man's reproductive potential. It is when females hide their reproductive stage by covering themselves with clothing that males become particularly interested in breasts. Breasts become erotic when hidden and their display is seen as a possible sexual invitation, in the same way that an exposed leg is seen as a possible sexual invitation in some societies. Brassieres are used, like dieting, hair dye, and plastic surgery, to influence a male into thinking that the female is of prime marriageable age. Breasts are aimed at potential husbands, not lovers. They signal wife potential, not erotic or immediate reproductive potential to "Coolidge Effect" driven males (see Symons 1979:189-190). Thus, we argue that if the timed reproductive sequence beginning at puberty is not fulfilled, a female begins to suffer the consequences of senescence earlier than she otherwise would. Developed breasts communicate the fact that a female is in her reproductive phase, that she can be impregnated and hence is marriageable; breasts can be seen by males as a necessary condition for getting pregnant. This "breast" communication is particularly important given the fact that h u m a n ovulation is hidden. The enduring nature of the h u m a n breast also enhances the ability of the female to get a new husband when her old husband dies. Thus, enduring breasts help ensure not only that she gets pregnant in a timely fashion, but that she stays in the pregnancy-nursing sequence. This article is based upon a paper presented at the Sixth Annual Scientific Meeting of the Human Behavior and Evolution Society, June 18th, 1994, University of
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Michigan, A n n Arbor. The authors wish to thank Blair Meredith Coe for her patient and thorough assistance in the preparation of m a n y aspects of this paper, and June-el Piper, assistant editor of Human Nature, for her thorough and very careful editing of this manuscript.
Kathryn Coe is a Ph.D. candidate in anthropology at Arizona State University and project director of an NCI grant focusing on cervical and breast cancer in Hispanic women. Field research for her doctoral dissertation focused on the health, fertility, and culture of the Chachi Indians of the coastal rain forest of Ecuador.
Lyle Steadman is an assistant professor of anthropology at Arizona State University. He has conducted research for more than two years among the isolated Hewa of Papua New Guinea. His research interests include evolutionary theory and culture, particularly religion and kinship.
NOTES 1. Mutations or loss of heterozygosity may have a strong influence on prognosis. An oncogene, HER-2/neu, is correlated with more aggressive tumor behavior and often overexpressed in w o m e n with breast cancer. Oncogene m53 may be associated with tumor suppression (Swanson 1992), while oncogene nm23 produces a protein which appears to inhibit the ability of breast cancer cells to spread throughout the body (Russo and Russo 1992). Loss of the nm23 gene may result in metastases leading to infiltrating ductal carcinomas and reduced survival time (Russo and Russo 1992; Swanson 1992). Allele loss correlated with poor prognosis also has been detected in chromosome 13 and 17. The retinoblastoma gene located in chromosome 13 has reportedly been deleted in approximately 30% of breast tumors. The short region of chromosome 17 has been deleted in u p to 65% of breast cancers, including cancer cell lines (Russo and Russo 1992). 2. As described for the Australian Tiwi, the first marriage of most y o u n g females is to an old, polygynous male. However, these y o u n g females get pregnant with remarkable regularity, no matter how old the h u s b a n d or how m a n y wives he has. Hart (1960) implies that m a n y of these pregnancies m a y be due to brief matings with young, unmarried men in the "bush."
REFERENCES Alexander, R. 1976 The Evolution of Social Behavior. Annual Review of Ecology and Systematics 5:325-382. Anderson, D., and M. Badzioch 1985 Risk of Familial Breast Cancer. Cancer 55:383-387. Andrieu, N., E Clavel, M. Auquier, B. Gairard, L. Piana, A. Bremond, J. Lansac, R. Flamant, and R. Renarud
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1993 Variations in the Risk of Breast Cancer Associated with a Family History of Breast Cancer According to Age at Onset and Reproductive Factors. Journal of Clinical Epidemiology 46 (9):973-980. Baanders, A., and E de Waard 1992 Breast Cancer in Europe: The Importance of Factors Operating at an Early Age. European Journal of Cancer Prevention 1:285-291. Bishop, D. 1993 The Involvement of Genetic Factors in Susceptibility to Breast Cancer. European Journal of Cancer Prevention 2 (supplement 3):125-130. Bowcock, A., L. Anderson, D. Black, et al. 1993 Polymorphisms in THRA1 and D17S181 Flank a
K a t h r y n Coe
Lyle B. S t e a d m a n
Hispanic Research Center Arizona State University
Department of Anthropology Arizona State University
This paper, u s i n g m o d e r n D a r w i n i a n theory, proposes an e x p l a n a t i o n for the i n c r e a s i n g l y high incidence of breast cancer f o u n d a m o n g preand p o s t - m e n o p a u s a l w o m e n l i v i n g today in w e s t e r n i z e d countries. A n u m b e r of factors have b e e n said to be responsible: genetic inheritance (BRCA-1), diet (specifically the increased c o n s u m p t i o n of dietary fat), exposure to carcinogenic agents, lifetime m e n s t r u a l activity, and reproductive factors. The p r i m a r y aim of this p a p e r is to demonstrate the value of a perspective based on D a r w i n i a n theory. In this paper, D a r w i n i a n theory is used to explore the p o s s i b i l i t y that the increased incidence of breast cancer is due p r i m a r i l y to the failure to complete in a timely m a n n e r the reproductive d e v e l o p m e n t a l cycle, b e g i n n i n g at menarche and c o n t i n u i n g t h r o u g h a series of pregnancies a n d lactation. O n the basis of comparative data, we a s s u m e that most w o m e n in ancestral p o p u l a t i o n s b e g a n h a v i n g c h i l d r e n before age 20 or so and t e n d e d to r e m a i n either p r e g n a n t or n u r s i n g for most of their adult lives. If a w o m a n did n o t have a child b y age 25 or so, she p r o b a b l y w o u l d n e v e r have one. Therefore, selection w o u l d p r o b a b l y not have acted against deleterious traits, such as cancer, that appeared after that age, just as it does not act against such traits in old age.
Received October 27, 1994; accepted January 23, 1995.
Address all correspondence to Kathryn Coe, Hispanic Research Center, Arizona State University, Tempe, AZ 85287-2702 Copyright 9 1995 by Walter de Gruyter, Inc. New York Human Nature, Vol. 6, No. 3, pp. 197-220. 197
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KEY WORDS: Breast cancer; Breast development; Darwinian theory; Human reproductive cycle.
Breast cancer is referred to as a disease of modern civilization, by which is meant that women living today in developed countries, or living a westernized lifestyle in developing countries, experience higher risk for this disease than do women living in tribal societies or third world countries (Learmonth 1988). Eaton et al. (1994) suggest that the risk of women living in industrialized societies may be as much as 100 times that of pre-agricultural women. This increased incidence has been said to be correlated with such things as diets that are increasingly high in saturated fat, contact with carcinogenic agents, hormonal events associated with menstrual activity or anovulatory menstrual cycles, a n d / o r reproductive factors. Findings, unfortunately, are confusing and contradictory, often because studies fail to focus on or examine the same variables (Rautalahti et al. 1993; I. Russo and J. Russo 1993). In this paper, Darwinian theory is used to formulate a hypothesis focusing on differences between the present environment and that of our evolutionary past. This hypothesis proposes that increased breast cancer risk is related to recent changes in the reproductive developmental sequence that is initiated at puberty and involves a series of pregnancies and lactation. To begin this discussion we need a definition and some relevant facts.
WHAT IS CANCER? Cancer begins when a single normal cell experiences particular kinds of genetic changes, called mutations, which result in loss of normal controls over key cellular processes, thus converting a normal cell into one whose descendants will all become cancer cells (Prescott and Flexer 1982). Cancer cells, unlike normal cells, grow and divide rapidly and irregularly; have an unstructured appearance; show abnormalities in the structure of DNA molecules; have the ability to invade adjacent, normal tissue; have greatly prolonged life spans; and do not perform normal functions in the body (Prescott and Flexer 1982). Cancer cells draw on the body's nutrient supplies but contribute nothing to the functioning of the body (Learmonth 1988). As cancer cells grow, neoplasms, or tumors, are formed. Breast cancer is a heterogeneous disease, the most common histological type of which is infiltrating ductal carcinoma (Russo and Russo
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1992), which appears to involve a continuum of histologic changes in the ducts of the breast. Such changes begin with ductal hyperplasia, which can progress to atypical hyperplasia, then to ductal carcinoma in situ, and finally to invasive carcinoma (Strah and Love 1992). Ductal carcinoma in situ (DCIS), referred to as a precancer, is characterized by malignant epithelial cells that fill the m a m m a r y ducts without disruption or involvement of the basement membrane; unlike invasive cancer, DCIS lacks the ability to invade or metastasize (Strah and Love 1992).
INCIDENCE Breast cancer is primarily a disease of human females; in males this disease is quite rare (Swanson 1992). Breast cancer is one of the most frequently diagnosed malignancies and is now the second leading cause of cancer mortality among westernized women. Incidence is high in Canada and the United States. Within the United States, average annual incidence in 1977-1983 was highest among Native Hawaiian women, whose rate was about 10% higher than among white women: 106.1 per 100,000 women, compared with an incidence in white women of 96.8. Incidence during this same period was lowest among Native American (21.3 per 100,000), Alaskan native (44.2), and Hispanic (52.1) women (Swanson 1992). In Europe, incidence is highest in France, Sweden, Denmark, Switzerland, the United Kingdom, and the Netherlands and lowest in Spain, Hungary, Romania, Poland, and Czechoslovakia (Baanders and de Waard 1992). During the period 1978-1982, the age-standardized rates in Europe ranged from 71.6 (per 100,000) in the Netherlands to 27.2 in Hungary. Incidence is low in India, Philippines, Kuwait, and in most Asian, African, and South American countries (Baanders and de Waard 1992; Kelsey 1979; Swanson 1992). Incidence of breast cancer in westernized countries appears to have increased significantly during the past few decades (Baanders and de Waard 1992) and may be reaching epidemic proportions (Marshall 1993; Nesse and Williams 1994; J. Russo and I. Russo 1993). In 1937, shortly after formal registration of this tumor was initiated, 58 per 100,000 women were diagnosed with breast cancer. In 1973, this number had increased to 83.9, and in 1988, to 112.9 (Swanson 1992). Although some of the increased incidence can be explained as screening effect, this source of bias cannot explain the long-term increase in breast cancer incidence because screening was not widespread until the mid 1980s (Colditz 1993). Further, screening effect cannot explain w h y breast cancer appears to be affecting younger women who are not regularly screened (Howe et al. 1989; Mayberry and Stoddard-Wright 1992).
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One recent study found that the risk of breast cancer increases among premenopausal women by about 11% each year until menopause, after which age becomes irrelevant (Rautalahti et al. 1993). Another study conducted in Washington found that for women aged 25--44 years, the incidence of breast cancer increased by 22% between 1974-1977 and 1982-1984, with an estimated annual increase of 2.5% (p < 0.001) (White et al. 1987). During these same periods, breast cancer incidence declined 12% for women age 45-54 years and 9% for women age 55 years and olden
RISK FACTORS Breast Cancer Is an Inherited Disease
One accepted risk factor of breast cancer is a family history of the disease (Anderson and Badzioch 1985; Bowcock et al. 1993; Kelsell et al. 1993; Kelsey 1979). Family history correlations m a y imply that similar environmental or social factors are operating (e.g., shared dietary habits produce similar endocrine or anthropometric features) (Kato et al. 1992; Swanson 1992); however, they also m a y imply genetic involvement. Although inheritance of BRCA-1, a marker found in the region between DNA markers D17S193 and D17S857 (Bowcock et al. 1993; Kelsell et al. 1993; Swanson 1992), does significantly increase one's chances of getting cancer (their lifetime risk may approach certainty) (Bishop 1993), inheritance explains only a small percentage of breast cancer cases, possibly less than 2% (Swanson 1992). 1
Breast Cancer and Contact with Environmental Toxins and Carcinogens
Carcinogens are agents that cause a statistically significant increase in the incidence of neoplasms when administered to individuals in a population of previously untreated organisms. These agents can be physical; biological, such as viruses; or chemical, such as complex hydrocarbons, aromatic amines, certain metals, chemicals that occur naturally in molds and plants, and hormones (Prescott and Flexer 1982; Rosenberg and Berry 1992; Russo et al. 1982). Chemical carcinogens appear to alter the DNA of the normal cell, thus modifying the content or flow of genetic information coded in the DNA's base sequence. Reactive electrophilic
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intermediates or carbonium ions appear to be formed during the metabolism of carcinogens. It is the reaction of these highly reactive intermediates with cellular components that may initiate the chain of events that results in cancer (Russo et al. 1982). The ultimate carcinogenicity of any compound seems to depend upon two factors: level of metabolites in target tissue available for interaction with critical cellular nucleophiles and presence of susceptible or nonsusceptible tissues (Russo et al. 1982). Susceptibility of the cell to undergo malignant transformation seems to be correlated with the rate of DNA synthesis and cell proliferation, and cellular competency in DNA excision repair (Russo et al. 1982). Developmental stages involving cell proliferation may be crucial, as cell proliferation is the driving force of tumor growth; carcinogens induce a greater response in dividing than in resting cells (Eaton et al. 1988; Russo and Russo 1988). Hormones, endogenous and exogenous, have been implicated in breast cancer because the development of many tumors appears to be hormone dependent; tumor growth can be suppressed by hormone deprivation, hormone administration, or pregnancy and lactation (Russo et al. 1990). Experimental studies using animals have shown that hormones can have a profound influence on breast tumor development; when human breast cancer cells are transplanted into mice, supplemental hormones must be administered if progressive epithelial tumor growth is to be sustained (Soule and McGrath 1980). Estrogens, which are ovarian hormones, have been implicated in breast cancer based on the assumption that their function is to initiate cell proliferation, whereas the function of progesterone is to inhibit estrogen receptors in the uterus, pituitary gland, and hypothalamus, and thus inhibit cell proliferation. However, recent studies have also implicated early high doses of progesterone in increasing breast cancer risk. In rats, a high dose of the estrogenic agent norethynodrel-mestranol was protective against the formation of tumors, while a similar dose of medroxprogesterone acetate increased tumor incidence (Russo and Russo 1988). At this point it is unclear whether estrogen or progesterone plays the stronger role in tumorigenesis, nor is it clear whether the role they play is an initiating one, a promoting one, or a growth-enhancing one. Recent studies of the sequence in which the particular hormones reach their target suggest that if they reach cells already affected b y a carcinogen, the hormones will act as promoters of tumorigenesis. If, on the other hand, hormones reach normal cells, they will induce differentiation of the breast (as explained later in this paper), thus eliminating the possible targets of carcinogens and abolishing the gland's potential for neoplastic transformation (Russo and Russo 1988).
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Breast Cancer and a Diet High in Saturated Fats
Circumstantial evidence for the etiologic role of dietary fat is found in immigration studies and studies of changes through time in diet. The increase in breast cancer found among offspring of Japanese emigrants to the United States can be correlated with subsequent changes in dietary habits (Kelsey 1979; Swanson 1992). When we examine the diet of the Bantu of South Africa, who consume approximately 15% of their calories from fat, the breast cancer mortality rate is 5 per 100,000 women, whereas among African-American women living in the United States, who consume a diet with 40% of the calories derived from fat, the breast cancer death rate is 23 per 100,000 (Swanson 1992). Further, the slow but steady increase in breast cancer incidence in the United States has been accompanied by a steady increase in dietary fat consumption (Kelsey 1979). Experimental studies using rats have shown that diets that are high in fat promote the development of both spontaneous and chemically induced breast cancer (Carroll and Khor 1971; Chan and Cohen 1974; Eaton et al. 1988; Tannenbaum 1942). This risk holds true at all ages (Swanson 1992). Although these studies indicate a correlation between fat consumption and breast neoplasms (Carroll et al. 1968), other studies, including a cohort study of 90,000 nurses, found no relationship between breast cancer and meta intake, calorie-adjusted total fat intake, or saturated fat intake and concluded that modification of dietary fat intake among adults was unlikely to reduce breast cancer risk (Colditz 1993; Willett et al. 1987). A recent meta-analysis concluded that high fat intake only has a modest effect on breast cancer risk (Howe et al. 1990). Such studies have led some major researchers to conclude that evidence supporting the fat-intake hypothesis just does not exist (Marshall 1993). One problem in the study of dietary fat is the fact that the mechanism by which dietary fat, or even stored body fat, increases breast cancer risk is unclear. High dietary fat consumption may exert an independent effect on breast cancer risk or it may act primarily through an influence on hormonal status (Swanson 1992). Dietary fat consumption appears to affect enteric reabsorption of steroid hormones by influencing the intestinal flora (Mansfield 1993). Obesity and body fat distribution also seem to increase estrogen levels (Swanson 1992). The breast tissue of obese women may be exposed to higher levels of estrogens owing to a lower production of 2-OH estrogen compounds; this may lead to a relative hyperestrogenic state (Tabar et al. 1985). An additional problem with dietary fat studies is that it is not clear if the effect of fats might be greater
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at the promotional stage of cancer or at the initiation of carcinogenesis (Kelsey 1979; Spiro 1993). Further, the relationship between variables such as age and dietary fat consumption typically have not been evaluated. Dietary fat may, for example, increase risk only if consumed in large amounts at particular ages. If dietary fat is related to increased breast cancer incidence via its influence on sex hormones, it is possible that fat consumption is critical at prepuberty and early puberty (Swanson 1992).
Breast Cancer and Lifetime Menstrual Activity In a number of studies, early menarche has been shown to increase risk for breast cancer. The age at menarche in the United States is estimated to have decreased by four months per decade during the period from 1840 to 1960 (Colditz 1993). Women in the United States and other industrialized societies tend to enter menarche two to three years earlier than women in countries like China (Wang et al. 1992). In China, w o m e n with their first menstrual period at age 12 years or earlier had an approximately 80% higher breast cancer risk than women who started menstruating at age 17 or later (Wang et al. 1992). In Tokyo, w o m e n who began to menstruate at age 13 years or younger had twice the breast cancer risk of women with menarche occurring after age 16 (Yuasa and MacMahon 1970). Age at menarche may be less important in determining breast cancer risk than the period of time elapsed between the onset of menarche and the birth of the first child. Baanders and de Waard argue that "almost 60% of the variance in breast cancer incidence in Europe can be explained by the length of the interval between menarche onset and the birth of the first child" (1992:289). Another study conducted in the United Kingdom found that intervals between menarche and first birth longer than 14 years significantly increased breast cancer risk in women over 61 (De Stavola et al. 1993). Early natural menopause has been said to confer a protective effect against breast cancer (Colditz 1993; Spiro 1993). Breast cancer patients have shown a higher mean age at natural menopause than women without breast cancer (Mansfield 1993). In Tokyo, women reporting menopause at age 50 years or older had a slightly higher risk of breast cancer than did women reporting menopause prior to age 50 (Yuasa and MacMahon 1970). In a study conducted in Burma, the trend toward increasing risk of breast cancer with increasing age at menopause was highly significant (p = 0.00003) (Thein-Hlaing and Thein-Maung-Myint 1978). Since increased risk for breast cancer appears to be correlated with both early menarche and late menopause, researchers began to focus on
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menstrual activity over the lifetime. One can estimate lifetime d u r a t i o n of m e n s t r u a l activity b y taking the years from m e n a r c h e to m e n o p a u s e and subtracting periods spent p r e g n a n t or lactating (Eaton et al. 1994; Nesse and Williams 1994; Rautalahti et al. 1993). It is not clear at w h a t point, or after h o w m a n y m e n s t r u a l cycles, a w o m a n ' s risk m a y increase. Some h a v e argued that risk m a y increase o n l y after a n u m b e r of years, perhaps after 30 years of m e n s t r u a l activity (Najem et aL 1982).
Breast Cancer and Full-Term Pregnancy Although some studies have indicated that parity has n o effect on breast cancer risk (Najem et al. 1982; Stavrakey a n d E m m o n s 1974; Talamini et al. 1985), others seem to lend strong s u p p o r t to the h y p o t h esis that parous w o m e n are at l o w e r risk for breast cancer than nonparous w o m e n ( H o w e et al. 1989). Since the 1970s, the inverse relationship b e t w e e n parity and breast cancer risk has been seen as principally a reduction in risk associated with early age at first birth. A striking reduction of breast cancer risk associated with h a v i n g a full-term pregnancy early in reproductive life was o b s e r v e d in data from a casecontrol s t u d y of 4,000 breast cancer cases and 12,000 controls from seven areas of the w o r l d (MacMahon et al. 1970). In a n u m b e r of other studies, first p r e g n a n c y before age 18 (Russo et al. 1982) or age 20 (Kelsey 1979; M a c M a h o n et al. 1970; S w a n s o n 1992; Thein-Hlaing and Thein-Maung-Myint 1978; Wang et al. 1992) was related to breast cancer risk. This r e d u c e d risk m a y be greater in prem e n o p a u s a l w o m e n (Kampert et al. 1988). First p r e g n a n c y at age 30 years or thereafter significantly increased risk (to 3.2 times the risk of w o m e n w h o s e first birth was before age 20) ( M a y b e r r y and S t o d d a r d Wright 1992; Salber et al. 1969; Thein-Hlaing and T h e i n - M a u n g - M y i n t 1978; Wang et al. 1992). W o m e n w h o s e first birth occurs at 30-34 years m a y have approximately the same risk as nulliparous w o m e n , and w o m e n w h o s e first birth is at age 35 or later m a y h a v e higher risk than nulliparous w o m e n (Mansfield 1993; M a c M a h o n et al. 1970). The early first p r e g n a n c y m u s t be full term if cancer risk is to be reduced. Pike et al. (1981) f o u n d a 2.4-fold increase in risk for breast cancer associated with first trimester abortion (spontaneous or i n d u c e d ) before the first term p r e g n a n c y (see also M a c M a h o n et al. 1982). Although findings are contradictory (see A n d r i e u et al. 1993; H o w e et al. 1989), a n u m b e r of studies do s u p p o r t that the risk of breast cancer increases significantly w h e n w o m e n experience an abortion prior to a first live birth (Brinton et al. 1983; Hadijimichael et al. 1986; H o w e et al. 1989; Lindefors-Harris et al. 1989; Parazzini et al. 1991; Pike et al. 1981).
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In Washington the breast cancer rate among poor w o m e n rose by 53% in the period 1974-1984, after the state started funding abortions (Cates 1982; Krieger 1990). Daling et al. (1994) suggest that the risk of breast cancer may be especially high if the female is younger than 18 and her abortion occurred after 8 weeks of gestation, or if the w o m a n was age 30 or olden Although many researchers claim, along with Baanders and de Waard (1992), that age at first birth is the most important, hormone-associated, risk-factor of breast cancer, recent studies point out that a pregnancy may initially boost the level of risk (Colditz 1993; Kampert et al. 1988; Lambe et al. 1994; Pike et al. 1983). Lambe et al. (1994) have proposed that pregnancy has a dual effect on breast cancer risk: increasing shortterm risk while conferring long-term protection.
Breast Cancer and Lactation
For centuries the claim has been made that the breast that never was used for nursing was more liable to become cancerous (see Doll 1975); however, evidence regarding this claim has been contradictory. In 1960s and 1970s, MacMahon and his associates found no important association between lactation and risk of breast cancer in data from a series of international case studies. Controlling studies for age of first pregnancy, they argued, caused any association to disappear. They concluded that the reported relationship between lactation and breast cancer could be explained by other intermediate variables, such as age, parity, and socioeconomic status (MacMahon and Feinleib 1960; MacMahon et al. 1973). Consequently, lactation generally was not regarded as an independent risk factor in studies of breast cancer (London et al. 1990). Recently, however, several researchers have reported that lactation m ay be associated with decreased risk of breast cancer (Byers et al. 1985; Kelsey and John 1994; Lubin et al. 1982). Wang et al. (1992) found that w o m e n in China w ho accumulated at least nine years of breast feeding had about one-sixth the risk of w om en who never nursed and one-half the risk of wo me n whose nursing time was three years or less. Risk decreased about 11% for each year of lactation experience, and this trend of decreasing risk with increasing months of lactation was highly significant (p for linear trend = 0.00003). McTiernan and Thomas (1986) have also claimed that there is a definite association between a longer experience of lactation and decreased risk of breast cancer, particularly in premenopausal women. And even MacMahon now supports the suggestion that there is a reduction in breast cancer among premenopausal w o men who have lactated (Newcomb et al. 1994).
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Cancer and Number of Full-Term Pregnancies Most researchers agree that breast cancer risk, after age 45, decreases with increasing parity (Kelsey and John 1994; Salber et al. 1969). In studies from Burma, Iceland, Sweden, and Buffalo, New York, high parity appears to offer additional protection beyond that offered by early age at first birth (Kalache et al. 1993; MacMahon et al. 1982). In Brazil (509 cases, 509 controls), increasing parity was strongly associated with decreasing cancer risk (p < 0.001) (Kalache et al. 1993). In China (300 cases, 300 controls), women with five or more full-term pregnancies had one-tenth the risk of women with just one full-term birth (Wang et al. 1992). This risk, which decreased with increments in full-term pregnancies (p for linear trend < 0.00005), decreased 22% with each full-term pregnancy (Wang et al. 1992). In Burma (193 cases, 400 controls), women who had six or more children had only one-third the risk of women with less than four children (Thein-Hlaing and Thein-Maung-Myint 1978). A study conducted in Estonia (322 cases, 694 controls) found that a second birth before the age of 25 was associated with a substantial and statistically significant reduction in risk, to one-third of the risk for a uniparous w o m a n who did not have a second child before that age (MacMahon et al. 1982). The risk for women having two births or more under the age of 25 years, after adjustment for age at first birth, was estimated to be 13% lower than for women who had only one birth under that age. Not only were subsequent births associated with additional protection against breast and also ovarian cancer, but the extent of protection depended on the subject's age at the time of the birth (MacMahon et al. 1982; Mori et al. 1988). There is some evidence of a synergistic effect of parity and age, suggesting that having a few children at a young age (before 30-33) can be protective (Remennick 1989). The low incidence of breast cancer in eastern European countries such as Estonia, which have low fertility, may be explained by early age at first birth. In Czechoslovakia, age at first birth is 22.39; in Hungary, 22.40; in Poland, 22.80; in Yugoslavia, 22.76; and in Romania, 22.30. These ages are contrasted with those in countries of high incidence. In Ireland the average age at first birth is 26.08, in the Netherlands it is 25.74, and in England and Wales it is 24.96 (Baanders and de Waard 1992).
A DARWINIAN HYPOTHESIS Although a coherent theory of breast cancer has yet to emerge, a number of interesting correlations have been pointed out, the strongest of which may be that between menstruation and breast cancer. In 1973,
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MacMahon et al. showed that the incidence of breast cancer is strongly correlated with the number of menstrual cycles experienced by w o m e n prior to their first birth. Unopposed estrogen, which is released during the menstrual cycle, seems to be the main carcinogenic agent. In 1976, Short argued that the high frequency of menstrual cycles experienced by women in industrialized societies is a deviation from the h u m a n ancestral strategy. Short argued that in recent hunter-gatherer (and, by extension, ancestral) societies, females began menarche later and had their first child at about age 19 or so, nursed for several years, and continued bearing children and nursing until menopause. Eaton et al. (1994) have recently developed Short's evolutionary perspective further to explain the increased incidence of h u m a n female reproductive cancers, including breast cancer. According to the evolutionary approach, an understanding of humans living today requires an understanding of the environment in which humans evolved, since all organisms are products of natural selection acting on traits in ancestral populations. If we assume that the life of women in tribal societies more closely resembles that of our distant ancestresses than does our present lifestyle, we can use comparative data from these societies to reconstruct the way in which our ancestresses most likely lived. To the extent to which the modern environment and behavior deviate from that past, problems in modern populations may be a consequence of such deviation (see Eaton et al. 1994; Nesse and Williams 1994; Williams and Nesse 1991). Given high infant mortality, in the past females optimized the number of their offspring to maximize the number of their descendants by being pregnant or nursing almost continuously between menarche and menopause. This strategy presumably included mechanisms that were selected to resist anything that would impede it. The reproductive strategy of ancestral females, involving a particular timed sequence beginning at menarche and continuing through a series of pregnancies and lactation, must have differed significantly from patterns found today. Today, it is not unusual for women to postpone first reproduction, at times into their late thirties, and to have only a few offspring, w h o m they may fail to nurse. Based on comparative ethnographic data, w o m e n in ancestral populations married young, near puberty, and began having children every few years until menopause. 2 Thus, an ancestral female who failed to have a child by age 25 or so probably would never have one; she most likely would be barren forever. Furthermore, if menopause is the result of natural selection and was, as some have suggested (e.g., Alexander 1976), designed to help a female maximize the number of her descendants by directing her care toward existing children rather than continuing to have children up to
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her death, there should be some selection against deleterious traits, such as cancer, even after menopause. Not until a female who has had a number of offspring approached her likely age at death would selection cease to operate against deleterious traits. However, because a female who has not had offspring by age 25 or so is unlikely ever to have offspring, selection would not necessarily work to strengthen her ability to resist deleterious traits. On the other hand, selection should continue to operate on a male up to his death, regardless of his reproductive history. Thus, deleterious traits, such as cancer, are likely to be selected against only up to the age when a female or male could no longer influence her/his reproductive possibilities (Medawar 1957). We propose that the key to understanding the increased breast cancer incidence in premenopausal women is failure to complete in a timely fashion their reproductive sequence, which begins at menarche and continues through a series of pregnancies and lactation until menopause. Daly and Wilson (1978) describe in detail how, from the zygote onwards, each developmental stage depends precisely on a prior stage. In addition, the duration of each stage may be crucial; natural selection seems to have favored not only a strict, but a timed, developmental sequence. Natural selection has operated on the release of hormones, including both progesterone and estrogen, to prepare a female for repeated pregnancies and lactation. These hormones should not be pathological when released in the timed, developmental sequence of our ancestresses. However, the correlation observed between breast cancer and menstruation may be consistent with this evolutionary perspective. Based on observations made in modern tribal societies, the assumption made here is that ancestral females seldom menstruated since they almost always were either pregnant or lactating. If, as some anthropologists have observed (Malinowski 1962), women often fail to become pregnant for a period of several years after they begin menstruating (see also Short 1976), one would expect to find evolved mechanisms to protect them during this period when all reproduction lies in the future. In summary, some additions can be made to Eaton et al.'s detailed and well-presented discussion (1994) that breast cancer risk is related to lifetime menstrual activity. First, by concentrating on menstruation we may fail to appreciate the complex changes occurring in the breast that make the breast resistant to the action of carcinogens, including hormones. Second, a focus on menstruation m a y not help us understand the significantly increased risk experienced by w o m e n whose pregnancy is terminated by an induced abortion. If any pregnancy decreases risk, then even a partial pregnancy should also decrease risk. Third, because a w o m a n should not be favored to resist any deleterious traits after being nulliparous through age 25 or so, she m a y lack
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resistance to a number of such traits, including other cancers. Finally, by focusing on menstruation, a likely association between breast cancer and the very early development and the persistence of the protruding human breast, unique among primates, is ignored. The following discussions, which begin with a description of breast development, will discuss these points.
BREAST DEVELOPMENT
Although breast development begins during the embryonic period, when the nipple epithelium develops, the m a m m a r y gland is not fully developed at birth. At puberty, changes in the breast are initiated under the influence of ovarian estrogens; the enlargement of the breast is the first external sign of impending puberty in girls (Short and Drife 1977). Although the breast achieves its adult size before menarche, it achieves full development and differentiation only after a pregnancy has occurred (Russo and Russo 1987). The breasts of either nulliparous or immature (premenarcheal) females are structurally undifferentiated; the most common structure (50%) in their breasts is the virginal lobule, or lobule type one. Type two lobules, which have a more complex morphology, evolve from type one lobules within one or two years after onset of the first menstrual period. During pregnancy, type three lobules evolve out of type two lobules. A fourth type of lobule (lobule type four), which appears during lactation, is considered to be the maximal expression of breast development and differentiation and the stage at which breast development is completed. According to Russo et al. (1992), the breast of nulliparous w o m e n is composed predominantly of type one lobules, whereas the breasts of parous w o m e n contain a high percentage of lobule type three. With the end of pregnancy, the cessation of lactation, and the process of aging, type three lobules regress to type one lobules. However, in the breasts of parous women, type one lobules exhibit lower proliferative activity than they do in the breasts of nulliparous women. The protective effect of pregnancy is through its effect on gland differentiation. In rats, the more differentiated the structures of the breast at the time of carcinogen (i.e., 7,12-dimethylbenz[a]anthracene, DMBA) administration, the more benign and organized is the lesion that develops (Russo et al. 1982). In humans, the site of origin for preneoplastic lesions such as atypical ductal hyperplasias, which may evolve through a series of changes to invasive carcinoma, is the terminal ductal lobular unit, which is equivalent to lobule type one. Type two lobules might originate atypical lobular hyperplasia and lobular carcinoma in situ.
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Type three lobules might be the site of origin for nonmalignant tumors such as fibroadenomas. These findings suggests that the degree of differentiation or lobular development of the breast influences the type of tumor developed (Russo et al. 1992). Differentiation of the breast may play a key role in carcinogenesis by affecting processes that are initiated at menarche, namely the high cell proliferative activity observed in the terminal end bud. During pregnancy, breast cells are shifted from the proliferating to the resting stage, the carcinogen-DNA binding is significantly reduced, the DNA repair is more efficient, and the cells produce less-polar metabolites. These biological parameters all influence the susceptibility of the m a m m a r y gland to carcinogenesis. Full differentiation of the gland induced by pregnancy may eliminate the targets of the carcinogen, and this protective effect is maintained after the termination of pregnancy (Russo et al. 1992). Multiparity serves to extend lobular development and decrease the density of terminal end buds. After administration of the carcinogenic agent DMBA, young virgin rats experience the highest incidence of tumors while multiparous rats experience the lowest incidence. In young virgin rats, 100% of tumors are adenocarcinomas; in old virgin rats, 63% of tumors are carcinomas; and in multiparous rats, 21% of tumors are carcinomas (Russo et al. 1982). This finding suggests that complete development and differentiation of the breast may require more than one full-term pregnancy. Early pregnancy may be crucial. Cell replication in the terminal ducts of the human breast has its highest peak during early adulthood; a history of parity between the ages of 14 and 20 may be related to a "significant increase" in the number of type three lobules (Russo et al. 1992). It is during this period of rapid cell growth that the breast is most susceptible to carcinogens (Russo et al. 1982). As one example, exposure of the breasts to radiation when a female is 10 to 19 years of age is associated with especially high risk, particularly if exposure occurs around menarche (Kelsey 1979). Since early pregnancy promotes gland differentiation early in life, it shortens the amount of time proliferating breast cells are vulnerable to carcinogenic stimulus (Russo and Russo 1991). The sequence of exposure to a carcinogen and the periods of high mitotic activity may help explain w h y parity may both increase and decrease risk. As one example, type two lobules evolve several years after puberty. If a young female who primarily has only type one Iobules gets pregnant, these lobules will not evolve into type three lobules, which only evolve from type two lobules. Such females may be at high risk for cancers related to exposure to pregnancy hormones, such as progesterone. In another example, pregnancy may increase the shortterm risk of breast cancer by promoting the proliferation of cells that
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have already undergone the early stages of malignant transformation (Lambe et al. 1994). However, pregnancy also may confer long-term protection against breast cancer by inducing breast differentiation. Since each pregnancy leads to an increase in the number of type three lobules, repeated pregnancies should provide significant protection against breast cancer.
INDUCED ABORTION
Menstrual factors do not appear to be able to account for significant increases in cancer risk that may be associated with an induced abortion (Brinton et al. 1983; Cates 1982; Daling et al. 1994; Hadijimichael et al. 1986; Howe et al. 1989; Krieger 1990; Lindefors-Harris et al. 1989; Olsson et al. 1991; Parazzini et al. 1991; Pike et al. 1981; White et al. 1994). If these studies hold true, induced abortion m a y increase cancer risk even in females who have experienced very few menstrual periods. Disrupted pregnancy abruptly halts the process of breast cell proliferation. This action, described by some authors as "hormonal blow," has a strong effect on the immune, nervous, and other systems (Remennick 1989). Although cell proliferation has been initiated, the process does not promote or culminate in complete differentiation of the breast, or eliminate targets of carcinogens (Russo and Russo 1980). In rat studies, the mammary glands of animals in which pregnancy was disrupted contain some areas with completely differentiated structures and other areas in which undifferentiated structures prevail (Russo et al. 1982). These animals had the same tumor response as did virgin animals to subsequent administration of DMBA. Russo and Russo (1980) hypothesize that incomplete differentiation of the cells of the m a m m a r y gland during the first trimester increases the subsequent susceptibility of breast tissue to carcinogenic agents.
SENESCENCE Senescence involves the shutdown or impairment of body systems, making organisms more susceptible to diseases such as cancer. Senescence typically begins late in life when organisms have completed reproduction; thus it would not be unexpected in postmenopausal women. Something much like senescence, however, also may occur in females who do not follow the timed developmental sequence. Like the appearance of deleterious traits when an organism approaches its physical death, such traits expressed in an individual who will never have offspring, perhaps
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beginning as early as age 25 in ancestral h u m a n females, would not have been selected against. In ancestral populations, prolongation of the stage of development between menarche and first full-term birth, for example, also would have led to few descendants. Genes coding for cell proliferation, valuable at the time of development, could be deleterious in nonreproductive females. Failure to suppress the rapid cell growth that marks the period between menarche and first full-term pregnancy would not be selected against in barren females, just as deleterious genes that have their effect near physical senescence are not selected against. Although no studies identified in the literature have addressed subsequent cancers or other diseases in premenopausal women diagnosed with cancer in one breast, it is known that women with cancer in one breast have four to five times the risk as comparable women of the same age of developing a second primary cancer in the other breast (Kelsey 1979). Also, younger women (age less than 40 years) who develop primary breast cancer are more likely to develop a second cancer than women who developed cancer at an older age, and they are slightly more likely to die of cancer (Swanson 1992). There is a twofold increase in risk of a second primary cancer in the ovaries, following breast cancer (Kelsey 1979). Multiple primary cancers involving the breast, endometrium, and ovary share important epidemiological characteristics and occur more frequently than one would expect by chance (Kelsey et al. 1981). Also, although the evidence is both unclear and contradictory, associations have been reported between breast cancer and subsequent soft tissue sarcoma, meningioma, malignant melanoma of the eye, acute myeloid leukemia, major salivary gland tumors, and cancers of the buccal cavity, pharynx, and thyroid (Kelsey 1979).
THE HUMAN BREAST
The final point, surely relevant to this entire discussion, was raised by Short and Drife in 1977: Why does the human breast, in contrast to that of all other primates, become fully anatomically developed at puberty, well in advance of the first ovulation or the first pregnancy? And w h y does the human breast, in contrast to that of all other primates, remain protruding throughout much of the remainder of her life? Clearly, as Short recognized, this is not explained by lactation. Short and Drife (as well as most others) assume that this early breast development is erotic, aimed at arousing males sexually. However, among the Hewa of the Highlands of Papua New Guinea, a society in which women are bare breasted, breasts are referred to as "milks"; they are not involved in sexual foreplay, and people of both sexes are bewildered when asked about
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breasts being erotic. The size and shape of breasts are symbolized by both males and females by placing their hands on their chest to identify the three most important stages of a woman's life: fists indicate her prereproductive phase, hands straight out indicate that she is in her reproductive phase, and hands down indicate her post-reproductive phase. What we are proposing is that breasts did not and do not remain protruding throughout much of an ancestral female or modern woman's life because they are sexually provocative; rather their existence and attitude indicate to a possible mate the female's reproductive potential, in the same way as her age, agility, health, and symmetrical appearance. That is, breasts communicate wife potential, not temporary sexual potential. When a male marries a female with full and upright breasts he can benefit from her entire reproductive output. As her breasts decline, they signal her declining reproductive potential, and hence her declining attractiveness as a wife. In a polygynous society, a female with upright breasts can choose to marry almost anyone she wants. Keep in mind that in a polygynous society all males are more or less continuously wife-seeking, and every wife gained increases a man's reproductive potential. It is when females hide their reproductive stage by covering themselves with clothing that males become particularly interested in breasts. Breasts become erotic when hidden and their display is seen as a possible sexual invitation, in the same way that an exposed leg is seen as a possible sexual invitation in some societies. Brassieres are used, like dieting, hair dye, and plastic surgery, to influence a male into thinking that the female is of prime marriageable age. Breasts are aimed at potential husbands, not lovers. They signal wife potential, not erotic or immediate reproductive potential to "Coolidge Effect" driven males (see Symons 1979:189-190). Thus, we argue that if the timed reproductive sequence beginning at puberty is not fulfilled, a female begins to suffer the consequences of senescence earlier than she otherwise would. Developed breasts communicate the fact that a female is in her reproductive phase, that she can be impregnated and hence is marriageable; breasts can be seen by males as a necessary condition for getting pregnant. This "breast" communication is particularly important given the fact that h u m a n ovulation is hidden. The enduring nature of the h u m a n breast also enhances the ability of the female to get a new husband when her old husband dies. Thus, enduring breasts help ensure not only that she gets pregnant in a timely fashion, but that she stays in the pregnancy-nursing sequence. This article is based upon a paper presented at the Sixth Annual Scientific Meeting of the Human Behavior and Evolution Society, June 18th, 1994, University of
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Michigan, A n n Arbor. The authors wish to thank Blair Meredith Coe for her patient and thorough assistance in the preparation of m a n y aspects of this paper, and June-el Piper, assistant editor of Human Nature, for her thorough and very careful editing of this manuscript.
Kathryn Coe is a Ph.D. candidate in anthropology at Arizona State University and project director of an NCI grant focusing on cervical and breast cancer in Hispanic women. Field research for her doctoral dissertation focused on the health, fertility, and culture of the Chachi Indians of the coastal rain forest of Ecuador.
Lyle Steadman is an assistant professor of anthropology at Arizona State University. He has conducted research for more than two years among the isolated Hewa of Papua New Guinea. His research interests include evolutionary theory and culture, particularly religion and kinship.
NOTES 1. Mutations or loss of heterozygosity may have a strong influence on prognosis. An oncogene, HER-2/neu, is correlated with more aggressive tumor behavior and often overexpressed in w o m e n with breast cancer. Oncogene m53 may be associated with tumor suppression (Swanson 1992), while oncogene nm23 produces a protein which appears to inhibit the ability of breast cancer cells to spread throughout the body (Russo and Russo 1992). Loss of the nm23 gene may result in metastases leading to infiltrating ductal carcinomas and reduced survival time (Russo and Russo 1992; Swanson 1992). Allele loss correlated with poor prognosis also has been detected in chromosome 13 and 17. The retinoblastoma gene located in chromosome 13 has reportedly been deleted in approximately 30% of breast tumors. The short region of chromosome 17 has been deleted in u p to 65% of breast cancers, including cancer cell lines (Russo and Russo 1992). 2. As described for the Australian Tiwi, the first marriage of most y o u n g females is to an old, polygynous male. However, these y o u n g females get pregnant with remarkable regularity, no matter how old the h u s b a n d or how m a n y wives he has. Hart (1960) implies that m a n y of these pregnancies m a y be due to brief matings with young, unmarried men in the "bush."
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