798

Dietary Fat, Fatty Acids and Prostate Cancer 1 David P. Rose* and Jeanne M. Connolly Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, New York 10595

International comparisons suggest a relationship between prostate cancer incidence and dietary fat, an inference sup ported by migration studies, the changing incidence rates and levels of animal fat consumption in Japan and the results from some cas~control studies. Overall, however, epidemiological studies have been inconclusive, and although prostate cancer is one of the hormone-dependent tumors, evidence of interactions between dietary fats and male endocrine function is incomplete. Laboratory experimentation has shown that n-6 fatty acids stimulate and n-3 fatty acids inhibit human prostate cancer cells in culture; also, feeding diets rich in marine oils suppresses growth of these cells as solid tumors in athymic nude mice. These growth effects of polyunsaturated fatty acids appear to involve both prostaglandins and leukotrienes and to interconnect with autocrine regulation by epidermal growth factor-related polypeptides. Lipids 27, 798-803 (1992). Prostate cancer is now the second leading cause of cancer deaths in males, and the most frequently diagnosed cancer among men in the United States (1). Moreover, because of the changing age distribution, there will inevitably be further increases in cases and prostate cancer-related deaths as time goes on. In general, the populations with a high incidence of prostate cancer are those of northern Europe, or of northern European origin, although African-Americans, even after adjustment has been made for disparity in socioeconomic status, constitute an important exception to this general rule (2). Intermediate in rank are the southern European countries and those of Latin America, while the Far East shows the lowest mortality rates. Yet, despite the pronounced differences in clinically manifest prostate cancer, and consequently in the mortality rates, cancers which are restricted to the prostate gland and have remained undiagnosed in life ("latent" or "histological" prostate cancer} are found at autopsy with about the same frequency in Japanese men as in white males in the United States, Canada, England and Austria (2). This observation was refined by Akazaki and Stemmerman (3) wh(~ having noted that the prostate cancer mortality rate for Japanese in Hawaii is closer to that of the American white population than to the rate for native Japanes~ performed a histological study of latent carcinoma of the prostate. They found no difference in the actual prevalance rates between the two groups, but larger lesions suggestive of rapid growth rates were more common among the migrants to Hawaii.

1Based on a paper presented at the Symposium on Lipids in Cancer held at the AOCS Annual Meeting, Baltimore, MD, April 1990. *To whom correspondence should be addressed at Division of Nutrition and Endocrinology, American Health Foundation, 1 Dana Road, Valhalla, NY 10595. Abbreviations: AA, arachidonic acid; BSA, bovine serum albumin; DHA, docosahexaenoic acid; EGF, epidermal growth factor; EPA, eicosapentaenoic acid; LA, linoleic acid; LT, leukotriene(s); NMU, Nnitrosomethylurea; PG, prostaglandin(s); PUFA, polyunsaturated fatty acid(s); TGF-a, transforming growth factor a. LIPIDS, Vol. 27, no. 10 (1992)

Jackson et aL (4) made a pathological comparison of p r o state cancers in high-risk African-Americans and low-risk black Africans. Included was autopsy material from 249 males in Ibadan, Nigeria, and 243 in Washington, D.C.; none had had clinically manifested prostate cancer. Small ("micr~ scopic") carcinomas of the prostate were detected with approximately equal frequency in the two groups, whereas invasive cancer was more common among the African-Americans. Another internationally based autopsy study compared the frequency and histopathological characteristics of latent prostate cancers in seven geographical areas (5). Small, socalled "focal:' latent carcinomas occurred with approximately the same incidence in Hong Kong, Singapor~ Israel, Jamaica, Uganda, Germany and SwederL However, although larger, diffuse infiltrating carcinomas within the prostate gland were common in the two European and in the Jamaican black populations, they were seen much less frequently in the two Chinese and the Jewish populatiorL From these results, it appears that diffuse latent carcinomas are very likely on their way to becoming clinically manifest, whereas focal latent prostate cancers are usually either extremely slow in their progression, or are truly in a state of growth arrest and potential regression. Carter et aL (6) have proposed that while phenotypic changes have occurred in the cells that constitute what is commonly designated a "focal latent carcinoma," a term which they avoid, additional events are necessary for the emergence of invasive clinical disease While the biological mechanisms which determine the step-wise progression of a few transformed prostatic epithelial cells to a life-threatening, clinically overt, cancer remain to be elucidated, one possibility is that dietary fat, or specific f a t t y acids, are involved in this process.

DIETARY FAT, OBESITY AND PROSTATE CANCER The putative involvement of dietary fat in breast cancer etiology is discussed elsewhere in this issue. Figure 1 shows that, overall, there is a fairly strong positive correlation between the mortality rates for breast and prostate cancer in different countries. Particularly noteworthy is the low risk for both of these forms of cancer in Japan, an oriental country which shares many of the environmental hazards of the western industrialized countries. Wynder e t al. (2) pointed out t h a t when Japanese males migrate to the United States their risk of dying of prostate cancer increases and suggested that adopting the typical American diet, relatively high in fat, might be a contributing factor. Similar arguments do, of course, apply to breast cancer. A r m s t r o n g and Doll (7) showed t h a t prostate cancer mortality rates for different countries were highly correlated with estimates of total fat consumption. Using nutritional data published by the Food and Agriculture Organization of the United Nations and international cancer mortality statistics prepared by Kurihara e t al. (8) we have confirmed and extended their observations. Figure 2 confirms that there is a strong correlation (r = 0.704} between available fat from animal sources for 28 countries,

799

REVIEW

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FIG. 1. The correlation between age-adjusted prostate and breast cancer mortality rates for 28 countries (r --- +0.619). The U.S. data are for whites only. AUS, Australia; A, Austria; FR, France.

FIG. 2. The correlation between age-adjusted prostate cancer mortality rates and estimates of daily animal fat consumption for 28 countries (r = -F0.704).

expressed as percent of total calories p e r c a p i t a per day, and the c o r r e s p o n d i n g age-adjusted p r o s t a t e cancer mort a l i t y rates. However, a relationship is completely a b s e n t w h e n only fats from vegetable sources are examined {Fig. 3). W h e n we s o u g h t correlations between the e s t i m a t e d c o n s u m p t i o n of various food g r o u p s in 30 different countries a n d p r o s t a t e cancer m o r t a l i t y rates, we f o u n d a s t r o n g positive correlation with milk, a m u c h weaker one with meats, and a s t r o n g negative relationship to the cons u m p t i o n of cereal p r o d u c t s (9). I n general, there is a s t r o n g correlation b e t w e e n fat c o n s u m p t i o n and e n e r g y intake. However, w h e n we exa m i n e d t h e d a t a for 28 countries, we f o u n d only a weak association b e t w e e n p r o s t a t e cancer m o r t a l i t y rates and e s t i m a t e s of daily caloric intake {9). Next, t h e sources

of e n e r g y were considered, and t h e results followed t h o s e observed for d i e t a r y fat; a s t r o n g positive correlation was seen w h e n only calories of animal origin were included (r = 0.68), whereas for vegetable-derived calories the relationship was a n e g a t i v e one (r = -0.44). A n u m b e r of case-control studies have been p e r f o r m e d to examine the relationships between p r o s t a t e cancer and d i e t a r y fat intake. Table 1 s u m m a r i z e s eight of these, all b u t one of which provide some s u p p o r t for t h e association. P a r t i c u l a r l y c o n v i n c i n g are t h e results f r o m studies (12,13,16) w h i c h showed a positive relationship between increasing estimates of fat intake and risk. T h e exception is a s t u d y f r o m J a p a n , which f o u n d no relationship between p r o s t a t e cancer risk a n d t h e c o n s u m p t i o n of m e a t and milk (17). Likewise, a prospective investigation of

TABLE 1 Dietary Fat and Prostate Cancer Risk: Case-Control Studies

Study: First author (ref) Rotkin ri0)

Study design 111 matched-pairs, hospital controls.

Schuman et al. (ID

Case control study.

Graham et aL (12)

262 cases and 259 hospital controls, excluding those with digestive diseases. All white.

Kolonel et al. (13)

243 cases and 321 population controls; all 5 ethnic groups in Hawaii included.

Heshmat et al. (14)

Age and race-matched case-control study, 181 pairs, all black patients. Food frequency questionnaire for when aged 30-49 and >150 years. Italian study of 166 cases and 202 hospital controls. 142 matched-pairs; population controls. White- and African-Americans. Japanese study of 100 cases and population controls.

Talamini et al. (15) Ross et aL (16) Mishina et al. (17)

Outcome Association with animal fats: excess intake of pork, dairy products, eggs. Higher intake of margarine and other high-fat foods. Association with animal fats: increasing intake of meats and fish. Statistically significant, and with a clear dose-response only for those >/70 yr, similar trends for those 70 years, positive dose-response gradient for total fat; gradient for total fat. Total and saturated fats higher at age 30-49 years, but not statistically significant at P < 0.05. Significant positive relation with milk, cheese and meat consumption. Higher (animal} fat intakes associated with increasing risk: positive dose-response. No association.

LIPIDS, VoI. 27, no. 10 (1992)

800 REVIEW (22). They observed a significant positive association with milk consumption, and suggestive b u t weaker ones for dairy products and m e a t consumption and risk of d e a t h from p r o s t a t e cancer. Obesity has been associated with breast cancer risk in most, b u t not all, studies of p o s t m e n o p a u s a l women (23,24), and the same relationship has been sought in studies of prostate cancer. The results of seven reports, three of which were positive, are s u m m a r i z e d in Table 2. Overall, it seems p r u d e n t to conclude on present evidence t h a t obesity is unlikely to be a strong risk factor for prostate cancer, and t h a t any positive association m a y be due to a third element which is c o m m o n to b o t h high b o d y weight and prostate cancer risk. al.

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FIG. 3. The lack of correlation between age-adjusted prostate cancer mortality rates and estimates of dally vegetable fat consumption for 28 countries.

122,261 J a p a n e s e males failed to detect any association between these two fat sources and risk (18). Despite these negative results, which could conceivably be due to the inaccuracy of dietary recall d a t a when obtained from a low-risk, homogeneous population, m o s t of w h o m are consuming low levels of the foods in question, an examination of time-trends in J a p a n does provide some indirect support for a relationship between dietary fat and prostate cancer risk. Wynder e t al. (19) reevaluated this aspect of cancer epidemiology and pointed out t h a t there has been a fourfold increase in fat consumption, notably from animal sources, in J a p a n since the early 1950s. While these dietary changes have occurred, prostate and breast cancer incidence rates have increased steadily since the late 1960s. But, on the other hand, when Severson e t al. (20) studied 7,999 men of J a p a n e s e ancestry born and living in Hawaii, whose prostate cancer risk has been calculated to be 10 times t h a t in J a p a n (21), dietary fat, e s t i m a t e d from 24-h recall data, was not found to be associated with prostate cancer. A large prospective s t u d y of 6,763 white A m e r i c a n Seventh-Day Adventists was performed b y Snowdon e t

HORMONES AND PROSTATE CANCER: RELATION TO DIETARY FAT

B o t h prostate and breast tissues are targets for endocrine action, and cancers arising from both of these sites possess steroid receptors and are hormone-dependent at some stage in their development. Suppression of estrogen activity is standard therapy for breast cancer, as is elimination of androgen stimulation in the case of prostate cancer. M a n y studies have been performed in an a t t e m p t to d e m o n s t r a t e abnormal hormone levels in blood from pros t a t e cancer patients, and, specifically, elevations in the s e r u m androgens. No consistent differences compared with the serum levels of healthy men of similar age have been detected, perhaps because these operate in early life and are no longer evident at the time of diagnois (27). The results of a s t u d y performed by Ross e t al. (28) provide support for this interpretation. They compared the total and nonprotein-bound (biologically available) serum testosterone levels in college-aged African-American and white-American males. The black men, who possess the highest risk of developing p r o s t a t e cancer in later life of all population groups worldwide, had significantly higher total and unbound testosterone levels. The authors considered the possibility t h a t dietary fat intakes were involved in this difference in circulating androgens, b u t concluded t h a t this explanation was unlikely because nutritional surveys in the United States have d e m o n s t r a t e d no real differences in dietary fat intakes between blacks and

TABLE 2 Obesity and Prostate Cancer Risk

Study: First author (ref) Wynder et al. (2)

Garfinkel (26)

Study design Case-control; 300 cases and 400 hospital controls. Retrospective case-control; 268 fatal cases and 536 population controls. Prospective; 336,442 American males.

Graham et al. (12) Snowdon et al. (22)

Case-control; ITable 1). Prospective; 6,763 Seventh-Day Adventists.

Talamini et

Italian case-control (Table 1).

Greenwald

Ross

et at.

et al.

aL

(25)

(15)

(16)

LIPIDS, VoI. 27, no. 10 (1992)

Case-control (Table 1).

Outcome No association. No association between college age body weight and later risk. Positive: mortality ratio 1.33 for those 130-139% above average weight. No association. Positive: compared with 90-109% ideal body weight, relative risk of 2.5 for those 130-249%. Compared with 95 kg. No association.

801

REVIEW whites when matched, as was done in their study, for socioeconomic status. Jackson e t al. (4) included serum hormone assays in their comparative study of blacks in the United States and Nigeria, and did find that the testosterone and estradiol concentrations were lower in African black prostate cancer patients compared with the corresponding controls. Moreover, among the controls there were trends for the testosterone, but not estradiol, levels to be higher among the African-Americans. Dietary data were not included in this investigation. There is, however, evidence that diet can influence blood hormone levels in men. Obesity is accompanied by red u c e d plasma testosterone concentrations (29,30); the percentage that is nonprotein-bound shows little or no change {30), but because the plasma sex hormone-binding globulin concentration in middle-aged men is negatively correlated with body weight (31), the absolute level of biologically active testosterone is not necessarily reflected in the percent distribution of binding. In any event, these observations do not provide a basis for concluding that obesity and increased androgen biological activity are related risk factors for prostate cancer. The Seventh-Day Adventist Church recommends t hat its members abstain from meat, consume eggs and cheese sparingly and use milk as a protein source. In the United States, male Seventh-Day Adventists have been found to have a considerably lower prostate cancer mortality rate than the general population (32). Howie and Shultz (33) used 3-d food records to assess the dietary intake of lactovegetarian and non-vegetarian Seventh-Day Adventists, and non-Seventh-Day Adventist omnivorous males, all aged 49-62 years. The three groups did not differ in their consumption of fat, but the vegetarians consumed more crude and dietary fiber. Their plasma testosterone and estradiol levels were both significantly lower than those of the other two groups of men and were inversely correlated with the estimates of dietary fiber. We have discussed elsewhere the relationships between dietary fiber and fat, and circulating hormone levels in the context of breast cancer (34). One study has been published in which men at risk of fatal heart disease were placed on low-fat, low-cholesterol and high-complex carbohydrate diets (35). After 26 d, their serum estradiol concentrations were reduced by an average of approximately 50%; perhaps unexpectedly, there were no changes in the testosterone levels. ANIMAL MODELS

Attempts to develop animal models for human prostate cancer have met with only limited success and have not really provided a stimulus for experimental studies of dietary factors and prostatic carcinogenesis on a par with those seen in breast cancer research (36-41). Pollard and Luckert (37) observed the spontaneous development of prostate cancers in a genetically susceptible strain of Wistar rats and obtained some indication for a promotional effect of a diet supplemented with linoleic acid (LA)rich corn oil so as to bring its total fat content to 20% (w/w). When the chemical carcinogen N-nitrosomethylurea (NMU) was administered, the prostatic tumor yield was increased, an effect which was enhanced by testosterone administration, and also by a high-fat diet (38,39). How-

ever, in another NMU-induced prostate cancer model developed by Bosland e t al. {40), different levels or types of dietary fat had no promotional effects on tumorigenesis (41). FATTY ACIDS, GROWTH FACTORS AND PROSTATE CANCER CELL GROWTH

Recent studies in our laboratory have indicated that the fatty acid composition of the diet, as well as the absolute amounts of fat consumed, may influence prostate cancer risk. Our interest in this possibility was stimulated by a combination of epidemiological observations and the results which we had obtained from related investigations into dietary fatty acids and human breast cancer cell growth (42,43). Prostate and breast cancer incidence rates have both been increasing in the United States, as well as in Japan. We postulated {44), as did others {45,46), that there might be a relationship between the rising breast cancer risk in these countries and an increase in the consumption of vegetable oils rich in LA. Although obviously highly speculative, these arguments may be applied also to carcinoma of the prostate. As a first approach to the issue, we have performed a series of experiments in v i t r o to examine the effects of both LA, an n-6 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two n-3 fatty acids, on the growth of human prostate cancer cells (47). The PC-3 prostate cancer cell line was responsive to LA, its growth being stimulated in a concentration-dependent manner over a 5-750 ng/mL range when the fatty acid was incorporated into serumfree, bovine serum albumin (BSA) supplemented culture medium. In contrast, the n-3 fatty acids inhibited PC-3 cell growth, an effect which was also dose-dependent and due to an arrest of proliferation rather than nonspecific toxicity. This inhibition in v i t r o was particularly interesting because we had shown previously that the growth of human prostate cancer cells as solid tumors in athymic mice is suppressed by feeding a diet containing (n-3)-rich Menhaden fish oil (48). There is some epidemiological support for a protective influence of n-3 fatty acids against both prostate and breast cancer. In a study from Japan, where fish traditionally provides the major source of animal protein, Mishina et al. (17) reported that a low consumption of seafood was associated with increased prostate cancer risk. Alaskan Eskimo men who eat large quantities of fish are at low risk for prostate cancer, as are Eskimo women for breast cancer (49). To examine this issue further in the context to breast cancer, Kaizer e t al. (50) made international comparisons and showed an inverse association between percent of calories from fish and disease rates a f t e r adjustment for dietary fat intake; on the basis of Figures 1 and 2, it is to be expected that this relationship would also apply to prostate cancer. The n-3 fatty acids compete with LA and its metabolic product arachidomic acid (AA) for enzymes which regulate eicosanoid biosynthesis {Fig. 4). We used pharmacological inhibitors of prostaglandin (PG) and leukotriene (LT) synthesis to demonstrate a requirement for both families of eicosanoids for normal human prostate cancer cell growth in vitro, and its stimulation by LA (47). Particularly LIPIDS, VoI. 27, no. 10 (1992)

802

REVIEW 12.50

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significant was the suppressive effect of esculetin (6,7-dihydroxycoumarin) on PC-3 cell growth, because this compound inhibits the lipoxygenase enzymes, and hence LT synthesis, but actually enhances production of the PG (51}. As shown in Figure 5, caffeic acid, which has similar effects on LT and PG biosynthesis {52}, is also an effective inhibitor of prostate cancer cell growth in vitro. Like PC-3 cells, the DU145 human prostate cancer cell line does not require the presence of androgens for its growth; it grows readily in the absence of serum and synthesizes both epidermal growth factor (EGF) and the related polypeptide transforming growth factor a (TGFa}. These two growth factors, which share the same cell membrane receptors, are secreted into the culture medium by the tumor cells {53). Both PC-3 and DU145 cells possess E G F / T F G - a receptors, and we s u g g e s t e d t h a t an auto-crine loop exists for the regulation of prostate cancer cell growth {47,53). More recently, we obtained direct evidence for such autocrine control by showing t h a t DU145 prostate cancer cell growth is suppressed if the E G F binding sites are rendered inaccessible to the llgands by exposing them to a receptor protein-blocking antibody (54). After prolonged passage in vitro, a subline of DU145 prostate cancer cells was obtained which, like PC-3 cells, is stimulated to grow by LA. Using this subline, we exLIPIDS, Vol. 27, no. 10 (1992)

amined the possibility t h a t a relationship exists between EGF-like polypeptide secretion by the cancer cells and this (n-6)-induced growth response (Fig. 4}. When AA is formed from LA, it is largely incorporated into the cell membrane phospholipids where it provides a reserve of substrate for eicosanoid biosynthesis. Mobilization of AA involves phospholipase A2, an enzyme which has been shown to be stimulated by E G F in BALB/c 3T3 fibroblasts {55,56}. Figure 6 shows the concentrationrelated growth stimulation of the DU145 subline when it was cultured in the presence of LA, and the suppression of this growth response when EGF/TGF-a binding sites were blocked with receptor antibody. Additional experiments will be required to demonstrate that this inhibition is associated with a reduction in eicosanoid biosynthesis and is reversible by high concentrations of exogenous EGF. C O M M E N T A R Y

The epidemiological evidence t h a t dietary fat is involved in determining prostate cancer risk is conflicting, and is of an inferential character. International comparisons show an association between prostate cancer mortality rates and estimates of the consumption of fats of animal, but not vegetable, origin. This distinction holds also for breast cancer (9), but in both cases the association could be a spurious one. More persuasive are the trends in prostate cancer incidence and dietary fat consumption in Japan and the consequences of migration to areas of high prostate (and breast} cancer risk. There is a need for investigations of dietary composition and prostate cancer risk which are analyzed to distinguish between the effects of fat and energy intakes. This is an important issue and could be examined by appropriately located case-control studies which provide an adequate range of dietary patterns. One such s t u d y was performed in northwestern Italy by Toniolo et al. {57}, and demonstrated a significant association between breast

803

REVIEW cancer risk and saturated fat c o n s u m p t i o n after adjusting for caloric intake. We have discussed the geographical variation in the prevalence and histological characteristics of p r o s t a t e cancer p a t h o l o g y at some length because c o m p a r a t i v e investigations of d i e t a r y c o m p o s i t i o n in relation to l a t e n t carcinom a of the p r o s t a t e would be e x t r e m e l y valuable. A n o t h e r t a r g e t for future studies should surely be t h e large difference in p r o s t a t e cancer risk for African-Americans and white Americans. A d i e t a r y - h o r m o n a l h y p o t h e sis of p r o s t a t e cancer e t i o l o g y is o b v i o u s l y s t r e n g t h e n e d if it provides a mechanistic explanation for this discrepancy. There is an u r g e n t need for carefully regulated experimental d i e t a r y studies into the effects of fat and fiber on male p l a s m a hormone levels. These should include b o t h y o u n g men, as a follow-up to the r e p o r t e d differences in s e r u m testosterone levels (28}, and middle-aged and older males, m a n y of w h o m will have preexisting l a t e n t carc i n o m a s of the prostate. A t t e n t i o n should also be focussed on the influence of different t y p e s of f a t t y acids on the b i o l o g y of h u m a n pros t a t e cancer cells. For this work, g r o w t h studies in v i t r o should be c o m b i n e d with e x p e r i m e n t s in v i v o u s i n g athymic n u d e mice. I t m a y be considered p r e m a t u r e to a t t e m p t d i e t a r y int e r v e n t i o n trials aimed at r e d u c i n g p r o s t a t e cancer risk. However, progress is being m a d e in t h e d e v e l o p m e n t of similar trials in b r e a s t cancer (58,59), a n d these will offer t h e o p p o r t u n i t y to include male m e m b e r s of t h e family in pilot studies and biochemical investigations.

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