Prostate cancer: The main risk and protective factors-Epigenetic modifications.

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Prostate cancer: The main risk and protective factors – Epigenetic modifications Le cancer de la prostate: les principaux facteurs de risque et les facteurs protecteurs – Les modifications épigénétiques Mawussi Adjakly a,b , Marjolaine Ngollo a,b , Aslihan Dagdemir a,b , Gaëlle Judes a,b , Amaury Pajon a,b , Seher Karsli-Ceppioglu a,b,c , Frédérique Penault-Llorca b,d , Jean-Paul Boiteux e , Yves-Jean Bignon a,∗,b , Laurent Guy b,e , Dominique Bernard-Gallon a,b a

Département d’oncogénétique, CBRV, centre Jean-Perrin, 28, place Henri-Dunant, BP 38, 63001 Clermont-Ferrand, France b ERTICA, EA4677, université d’Auvergne, 28, place Henri-Dunant, 63001 Clermont-Ferrand, France c Département de toxicologie, faculté de pharmacie, université de Marmara, Istanbul, Turkey d Laboratoire de pathologie médicale, centre Jean-Perrin, 58, rue Montalembert, 63000 Clermont-Ferrand, France e Département d’urologie, CHU Gabriel-Montpied, 58, rue Montalembert, 63000 Clermont-Ferrand, France

Abstract With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial – there are nonmodifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet–cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Prostate cancer; Diet; Phytoestrogens; Risk factors; Epigenetics

Résumé Avec 13 millions de nouveaux cas recensés dans le monde chaque année, le cancer de la prostate apparaît comme un problème de santé publique. C’est une pathologie fréquente chez l’homme de plus de 50 ans et qui représente la sixième cause de mortalité par cancer chez l’homme dans le monde. Le cancer de la prostate à l’instar des autres types de cancer est une pathologie multifactorielle. Des facteurs non-modifiables tels que l’hérédité, l’appartenance ethnique, la localisation géographique ont été rapportés, mais il existe d’autres facteurs de risque modifiables tels que l’alimentation. Le rôle de l’alimentation dans la survenue des cancers suscite depuis quelques années un intérêt croissant. Le postulat de l’alimentation dans le déterminisme des cancers vient de données épidémiologiques qui font état d’une différence d’incidence de nombreux cancers entre les populations. En effet, des corrélations ont été établies entre une alimentation riche en graisses et la survenue de cancers hormonodépendants comme le cancer de la prostate et le cancer du sein. L’alimentation constitue un facteur de risque pour le cancer de la prostate. Cependant, des micronutriments contenus dans certains aliments sont considérés comme facteurs protecteurs vis-à-vis de la pathologie cancéreuse. Parmi ces micronutriments, on retrouve par exemple le lycopène dans la tomate, l’épigallocatéchine gallate dans le thé vert et les phyto-œstrogènes dans ∗

Corresponding author. E-mail address: [email protected] (Y.-J. Bignon).

http://dx.doi.org/10.1016/j.ando.2014.09.001 0003-4266/© 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Adjakly M, et al. Prostate cancer: The main risk and protective factors – Epigenetic modifications. Ann Endocrinol (Paris) (2015), http://dx.doi.org/10.1016/j.ando.2014.09.001

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le soja. Ces micronutriments exerceraient une action protectrice via des actions anti-oxydantes, une inhibition de la prolifération cellulaire. Ici, nous nous sommes particulièrement intéressés aux effets des phyto-œstrogènes notamment à la génistéine et à la daidzéine qui sont les deux plus étudiées en nutrition. Les phyto-œstrogènes du soja sont des molécules non-stéroïdiennes qui ont la capacité de mimer les effets du 17␤ œstradiol du fait de leur similarité de structure. Outre les effets antioxydants, les phyto-œstrogènes du soja auraient la capacité de moduler les modifications épigénétiques retrouvées dans le cancer de la prostate. Nous avons aussi étudié l’impact des phyto-œstrogènes sur les modifications épigénétiques notamment la méthylation de l’ADN, la régulation par les miARNs et les modifications des histones dans le cancer de la prostate. © 2014 Elsevier Masson SAS. Tous droits réservés. Mots clés : Cancer de la prostate ; Alimentation ; Épigénétique

1. Introduction The prostate is a small male sex gland found beneath the urinary bladder, at the crossroads between urinary tract and genital tract. About the size of a walnut, the normal adult prostate weighs 20–25 g and helps produce a nutritive medium for sperm. The prostate secretes seminal fluid that, along with the seminal plasma secreted by seminal vesicles, contributes key compositional components of semen. The seminal fluid comprises an array of proteins, including prostate-specific antigen (PSA), which serves as a molecular biomarker in screening tests for prostate disease. The secretion of seminal fluid provides nutrient energy for the spermatozoa and lends the semen fluidity. The prostate is an exocrine gland divided into three glandular regions called ‘zones’ – a peripheral zone, a transitional zone, and a central zone – sheathed in a fibroelastic stroma capsule. The prostate is essentially considered a hormone-dependent organ, as its growth, development and all-round function are dependently controlled by the plasma concentration of the male sex hormone testosterone. It has been established that embryonic prostate only differentiates in response to androgen secretion from fetal testes. Prostate size is seen to increase in older men (aged 50–60 years), and this increase may be a sign of benign prostatic hyperplasia (BPH) or prostate adenocarcinoma, which hits about a million men every year in France. BPH is a benign age-related increase in prostate size that can lead to urinary disorders. An abnormally large prostate can also be a sign pointing to prostate cancer tumors. Prostate cells – particularly the cells in the peripheral zone – can undergo genetic alterations and give rise to cancer cells. The peripheral zone of the prostate is the zone where 70% of prostatic cancers develop. The tumour cells then proliferate uncontrollably, and can ultimately increase prostate size. Cancer is a disease that involves an abnormal proliferation of tumour cells. Prostate cancer – like breast cancer – is a hormone-dependent cancer. 2. Epidemiology of prostate cancer 2.1. Incidence Prostate cancer ranks as the most common cancer diagnosed in men in France, with 71,000 new cases in 2011, accounting for 34% of all male cancers. The last decade has seen a surge in the incidence of prostate cancer worldwide (Fig. 1), and France is no exception. Over the 1980–2005 period, the incidence rate

Fig. 1. Worldwide incidence of prostate cancer from Globocan 2008 [2]. A higher incidence at around 174 is observed in post-industrialized nations, especially Europe and the USA.

of prostate cancer jumped from 26 to 123 cases per 100,000 persons [1]. This rise in incidence figures stems from a combination of aging population and improved diagnostic measures enabling early prostate cancer screening. One such measure is the total PSA assay. PSA – prostate-specific antigen – is a glycoprotein secreted exclusively by prostate cells, and the assay now enables doctors to diagnose prostate cancer even before symptoms appear. 2.2. Mortality At close to 3 million fatalities in 2008, prostate cancer is the sixth-leading cause of cancer deaths in males worldwide [2]. Figures for France put the number of prostate cancer deaths at 8700, which ranks it as the second-leading cause of cancer-related death in French men. In developed countries, while incidence rates continue to climb, mortality rates have dropped over the last few years – a paradox essentially explained by improvements in diagnostic tests that enable early patient management, but also by improvements in therapy. However, in less developed regions of the world like Sub-Saharan Africa, prostate cancer mortality rates remain high [3].




3. The main risk factors Prostate cancer is defined as a multifactorial disease, as it enrols not just genetic and biological factors but also environmental and personal lifestyle factors. Some of the risk factors for prostate cancer are non-modifiable – age, genetic predisposition and ethnicity – but others, such as diet, are modifiable.

Table 1 Hereditary prostate cancer – predisposing genes and known mutations. Predisposing genes common to prostate cancer and other cancers: breast cancer and brain cancer [9]. Disease or comorbidity

Genes (locus)

Mutations/Variants

Hereditary prostate cancer

HPC1/RNAS EL (1q24-25)

Mutations: E265X, MetIIe, 471delAAAG; Variants: Arg462Gin, Glu541Asp Unidentified Unidentified Unidentified Mutations: Arg781His, 1641insG, Glu216stop Variants: Glu622Val, Ser217Leu, Ala541Thr Mutations: Arg293X, Asp174Tyr, Pro36AIa, Ser41Tyr, Val113Ala, Gly369Ser, His441Arg Variants: Pro275Ala, PRO3, INDEL1, IVS5-59, INDEL7

3.1. Age Before 50 years of age, the proportion of men with prostate cancer is very low. In most cases, the disease gets diagnosed at age 65 or more. In the United States for example, 30.7% of men in the 55–64 years age bracket have prostate cancer versus just 0.6% for the 35–44 years bracket [4]. Prostate cancer thus qualifies as an older man’s disease and a significant public health issue in post-industrialized nations with greying populations.

PCaP (1q42-43) HPCX (Xq27-28) HPC20(20q13) (17p11)

3.2. Genetics and prostate cancer Familial forms account for less than 20% of prostate cancer cases, although hereditary transmission fitting a Mendelian inheritance pattern is only found in 5% of cases. Excluding earlyage onset, hereditary forms of prostate cancers present no single specific clinical-anatomic sign differentiating them from sporadic forms [5]. Hereditary transmission occurs through one of two modes – either as an autosomal dominant syndrome (transmission by the affected father) or as a sex-linked syndrome (transmission by the mother down to all her sons, who will subsequently not then transmit predisposition down to their own sons). There is genetic heterogeneity in the familial form of prostate cancer, as several predisposing genes have been discovered in different gene loci. The first description of a susceptibility gene was published by Xu in 2000. Xu’s team managed to show that a gene mapping to chromosome 1 – the gene they called HPC1 (hereditary prostate cancer 1) – was a hereditary prostate cancersusceptibility gene [6]. Another predisposing gene called PcaP (predisposing for prostate cancer), which also mapped to chromosome 1, was later discovered by European teams in 1998 to 2001[7,8]. Since then, several predisposing genes have been identified in various chromosomal regions [9]. Epidemiology studies point to a relationship between hereditary prostate cancer and other cancers (breast cancer, brain tumors, digestive system cancers), where the association is based on predisposing genes shared by these different cancers (Table 1) [10,11]. Men who have a first-degree relative with breast cancer appear to have a 1.4-fold higher risk of developing prostate cancer. Mutations in the BRCA2 gene associated with breast cancer are reportedly found in 2% of men presenting early-onset prostate cancer [12]. A mutation in the CAPB gene predisposing to brain tumour is also reported as predisposing to prostate cancer. 3.3. Ethnicity The incidence of prostate cancer varies significantly with geographic location. According to Globocan data, prostate cancer rates are lower in Africa and Asia than in Europe and the

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PG1/MSR1 (8q 22-23)

Hereditary prostate cancer/breast cancer Hereditary prostate cancer/brain cancer

BRCA2 (13q12-13)

6051delA (exon11), 999del5, 617del5

CAPB (1q36)

Unidentified

United States. Furthermore, incidence also differs between ethnic subgroups within national boundaries. In the United States, African-American men have a 60% higher risk for developing prostate cancer than their white counterparts [13]. This disparity appears to be linked to polymorphisms in genes involved primarily in hormonal regulation and development of the prostate [9,14,15]. 3.4. Environmental exposure disruptors Among the risk factors for prostate cancer, besides the elderly, the nutritional and genetic (familial and ethnic) ones, the environmental exposure disruptors (EED) have to be considered. 3.4.1. Bisphenol A The bisphenol A (BPA), like diethylstilbestrol (DES), is a synthetic estrogen, able to mimic and to interfere with hormone receptors. BPA was extensively used in the manufacture of polycarbonate plastics and epoxy resins. Due to incomplete polymerization to high temperatures, BPA leaches out from food and beverage containers, as well as dental sealants. Exposure to nanomolecular concentrations of BPA is ubiquitous via different ways: oral absorption, air, skin.




So, the prostate gland is hormone-dependent, classically with androgen but estrogen control through normal and tumour prostate development is supported by many data. Fetal or perinatal BPA or DES exposure in rodents, are associated in adults with prostate hyperplasia or pre-malignant lesions [16]. This perinatal exposure to BPA, like estradiol, increases the susceptibility to develop a prostate cancer spontaneously or after a second estrogenic contact [17]. It has been demonstrated that cancer cell lines became sensitive to BPA, activating proliferation through a mutation in the androgen receptor [18]. 3.4.2. Chlordecone A case-control study performed in French Antilles, reported the risk factors of chronic exposure to chlordecone, an estrogenic organochlorine pesticide in the development of prostate cancer [19]. Chlordecone or kepone has been widely used during 1973 to 1993 in the culture of banana. It will persist in groundwater during several decades. In men, this study allowed to demonstrate statistically the relation between chlordecone exposure and prostate cancer risk. 3.4.3. Pesticides Occupational exposure to pesticides has been associated with increased prostate cancer risk [20–22], for both private (farmer) and commercial applicators in the Agricultural Health Study. Koutros et al. observed significant increases in the risk of aggressive prostate cancer associated with 4 insecticides: fonofos (organophosphate), malathion (organophosphate), terbufos (organophosphate), and aldrin (organochlorine) in Iowa and North Carolina. In addition, a significant increase in risk of prostate cancer was found respectively with fonofos and aldrin among those with a family history of prostate cancer [22]. Organophosphate insecticides such as fonolos and terbufos are metabolized to their highly toxic oxon intermediate and are associated with DNA damage [23,24]. Organochlorine insecticides are endocrine disruptors that accumulate in adipose tissue, providing continuous endocrine perturbation that may increase prostate cancer risk [25]. 3.5. Diet The best-research environmental factor so far is the impact of diet on onset of prostate cancer. The first time diet was suggested to play a direct role in the onset of prostate cancer dated back to 1991, when Muir et al. [26] showed that Japanese and Chinese migrants to the US had a greater incidence than their ‘home’ populations and an equivalent incidence to their ‘host’ US population. This prompted the hypothesis that environmental changes – chiefly in diet – could explain the observed jump in incidence. Various studies tackling the diet issue have led to a scheme under which foods are qualified as pro-cancer or anti-cancer. 3.5.1. Animal fats and vegetable oils Among the at-risk foods, excessive intake of animal fats can play a role in the onset of prostate cancer. This linkage has been surfaced by case-control studies and by retrospective studies

[27,28]. Excessive intake of saturated fat accelerates the risk of relapsing prostate cancer after prostatectomy [29], whereas a high-energy input of 10% saturated fat can reduce PSA counts in men with prostate cancer. Intake of unsaturated fatty acids, especially ␻-6 fatty acids sourced largely from vegetable oils, is also associated with a high risk of prostate cancer [29]. Conversely, intake of ␻-3 fatty acids sourced primarily from fish is associated with a reduced risk of prostate cancer [30]. 3.5.2. Dairy products A cohort study led in France found evidence of a relationship between milk-source calcium and prostate cancer risk, in which the calcium content of milk aggravates prostate cancer risk [31]. Note that other epidemiology and case-control studies have shown a positive correlation between high calcium intake and risk of developing prostate cancer [32–34]. 3.5.3. Vitamins and minerals Numerous studies converge to show that certain vitamins could have a preventive effect against prostate cancer. D and E are the vitamins cited. Cohort and case-control studies have shown that vitamin D reduced the risk for prostate cancer [35]. For vitamin E, a prevention study led by Heinonen et al. (1998) showed that dietary intake of 50 mg/d ␣-tocopherol (a form of vitamin E) cut the risk of developing prostate cancer by 32% [36]. For mineral micronutrients, only selenium supplementation can significantly reduce (63%) the incidence of prostatic cancer [37]. Looking at the combination of vitamin E plus selenium, a study by Lippman et al. (2009) reporting on the Selenium and Vitamin E Cancer Prevention Trial (SELECT) was unable to find any real protective benefit of selenium plus vitamin E to prevent prostate cancer [38]. However, data from this same SELECT trial data updated for 2011 found that dietary supplementation with vitamin E significantly increased the risk of prostate cancer. The updated report was led with a longer follow-up and a cohort of more prostate cancer events than the initial SELECT report [39]. Epidemiological studies on zinc give divergent results and fail to conclude on a putative effect of zinc on prostate cancer. 3.5.4. Fruit and vegetables Fruit and vegetables are a source of micronutrients with potentially beneficial effects in the prevention of prostate cancer. The micronutrients contained in fruit and vegetables like la tomato, carrot, pomegranate and onions reportedly have antioxidant and antiproliferative effects on prostate cancer cells. Experimental studies have shown that pomegranate extract induced dose-dependent inhibition and apoptosis in a continuous prostate carcinoma cell line. These results were confirmed by an in vivo study led in nude mice showing significant inhibition in tumour growth following oral administration of pomegranate fruit extract [40]. The organosulfur compounds in garlic and onions are reported to have an inhibitory effect on prostate tumour cell growth in cell cultures [41]. There are reports that a compound called isothiocyanate, found in Brussels spouts, cabbage and broccoli, is able to inhibit the proliferation of prostate




cancer cells [42]. Evidence has been reported that grapeseed and wine inhibit prostate tumour cell growth [43]. Another micronutrient that has attracted a great deal of interest is lycopene. Lycopene is a member of the carotenoid family of pigments. It is typically found in tomato and other red fruit like watermelon, as well as mango and papaya. Lycopene – like all carotenoids – is touted as having potent anti-oxidant properties against prostate cancer [44]. Case-control studies led in China and the United Sates have shown a reduced risk for prostate cancer in people who eat more lycopene-rich foods [45,46]. However, a large Dutch cohort study was unable to find a relationship between lycopene intake and risk of onset of prostate cancer [47]. 3.5.5. Green tea Green tea contains potent anti-oxidant polyphenols and catechins like epigallocatechin gallate (EGCG) that are reported to reduce prostate tumour cell growth in cell cultures. This reduction in cell growth and proliferation is likely mediated by cell cycle arrest. The literature also reports evidence for an antiapoptotic effect of green tea polyphenols [48,49]. 3.5.6. Soy phytoestrogens Phytoestrogens are non-steroidal compounds found in plantbased foods – where soy-based products offer the most dietaryrelevant amounts – and that share structural similarity to 17␤estradiol (E2). The soybean is a climbing plant member of the Fabaceae family widely grown for its oilseed. It is native to south-east Asia and can integrate human diet in a range of forms. The recent surge in research into phytoestrogens stems from their estrogenic potency and their ability to mimic the effects of estrogens – the endogenous hormones naturally synthesized by humans. The phytoestrogens described in the literature encompass several plant-world compounds that, although structurally different, share structural similarity with E2 – the endogenous human estrogen. This structural similarity enables them to induce similar physiological effects to natural endogenous estrogens. Their estrogenic potential first came to light in 1940 when Australian sheep that had pastured copious amounts of red clover started to show disrupted reproduction and lactation. Phytoestrogens are found in several classes of compounds, including isoflavonoids, coumestans and lignans, all of which are collapsed into the larger structural group of polyphenols characterized by the fact that they possess one or more aromatic rings. Their polyphenol structure lends them anti-oxidant properties that hold great promise for the prevention and treatment of cardiovascular disease, neurodegenerative disease, and cancer. 3.5.6.1. The coumestans subclass. Coumestans are found in a variety of plants like clover sprouts, alfalfa, and green bean seeds. Coumestans are phytoalexins that plants accumulate in response to fungal or bacterial attack. Phytoalexins are antimicrobial substances synthesized de novo by the plants exposed to attacking organisms. The two most intensively-studied coumestans are coumestrol and 4’methoxy-coumestrol. Furthermore,

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coumestrol is the only one of these compounds with an estrogenic activity [50]. 3.5.6.2. The lignans subclass. Lignans are diphenols with a 2,3-dibenzylbutane skeleton. The lignan subclass features only two compounds considered as phytoestrogens – enterodiol and enterolactone. Both are enterolignans that are metabolites of their respective lignans, i.e. secoisolariciresinol and matairesinol [51]. 3.5.6.3. Stilbenes. Stilbenes are polyphenols found in an array of plant sources. By far the most important stilbene is transresveratrol, which is naturally present in grape skin and wine [52]. 3.5.6.4. Isoflavonoids subclass. Isoflavonoids are a subset of the flavonoids family whose common backbone structure is a flavone nucleus comprised of two benzene rings linked through a heterocyclic pyran ring. The parent class of flavonoids counts over 9000 compounds divided into 6 subclasses: flavonols, flavones, flavanones, flavanols (or ‘catechins’), anthocyanins and isoflavonoids (Fig. 2) [53,54]. These different classes of compounds are found in various food sources such as tea, wine, oil and soy [55]. Isoflavonoids are the major class of phytoestrogens. The two isoflavonoid phytoestrogens most intensively researched to date and most relevant to our study here are genistein and daidzein. Phytoestrogens are not synthesized by the organism but are sourced through diet. The isoflavones genistein and daidzein are found in a number of legume plants such as

Fig. 2. The main subclasses of flavonoids.




Table 2 Variability in phytoestrogen contents in soy-based foods [164]. Food

Quantity of genistein (␮g/100 g food)

Quantity of daidzein (␮g/100 g food)

Tofu Tonyu Soy-based desserts

14,770 3730 17,475

10,316 3402 17,300

peas and lentils, but the most phytoestrogen-rich food source is soybean seed. The highest phytoestrogen content, found in soybean, is in the range 10–30 mg (Table 2). Phytoestrogen contents in soybean or soy-based food can also vary widely – a variability explained by the soy-based ingredients used to produce these foods, as phytoestrogen content is higher in soybean seedbased products than in soy protein-based products. Other foods deliver only trace quantities of phytoestrogens, at around just a few hundred micrograms. Fruit, for instance, contains less than 5 ␮g genistein and daidzein per 100 ␮g. Furthermore, isoflavone input varies with geography. Asian populations that traditionally eat a lot of soy have high phytoestrogen intakes (45 mg/day for Japanese, 35 mg/day for Chinese) whereas Western-world

nations have extremely low phytoestrogen intakes (averaging out at just 0.4 mg/day) [56]. 3.5.7. Metabolism and bioavailability of soy isoflavones: genistein and daidzein The soy isoflavones found in plant tissue occurs as glycosides, i.e. bound to sugars. The main glycosylated forms of soy phytoestrogens are genistein and daidzein. Genistein and daidzein in plant tissue can also occur in acetylated or malonylated forms. Another isoflavone – glycitin – is found in soy, but has so far attracted little research (Fig. 3). As the glycosylated form is biologically inactive, the soy isoflavones get deglycosylated to cross the intestinal barrier. The deglycosylation or hydrolysis of soy isoflavone glycosides is performed by digestive tract bacteria but also by enterocyte enzymes like ␤glucosidase [53,57]. Hydrolyzed genistein and daidzein become aglycone or aglucone forms that are biologically active and can cross the intestinal barrier and into the bloodstream. A fraction of isoflavones can also migrate towards the liver to where they will be biotransformed before being excreted through blood or bile. The deglycosylated isoflavones thus get taken

Fig. 3. Structures of soy isoflavones. Isoflavones mostly occur as glycosylated, malonylated or acetylated forms that – once hydrolyzed – yield biologically active aglycone forms [164].




up in the liver, to be metabolized by the phase-I and phase-II detoxification enzyme systems. These enzymes are classically involved in removing steroids and polyphenols. When dealing with isoflavones, the phase-I enzymes and especially the phase-II enzymes will orchestrate isoflavone glucuronidation or sulphatation. In mammals, glucuronidation tends to be the most common form. Glucuronidation adds glucuronide groups to the hydroxyl functions of the isoflavones, leading to a more water-soluble form, thus facilitating subsequent transport into the blood and urinary clearance [58]. Further biotransformations can also take place downstream of the liver, as isoflavones derived from hepatic recycling reach the bowel. At gut level, the bacterial flora can metabolize daidzein to equol, which is a more active compound than its precursor [59]. Although many mammals (rats, mice, pigs) are able to convert daidzein to equol, not all humans can. In reality, only 30–50% of people are able to metabolize equol from daidzein [60]. The hypothesis has been put forward that the ability of these people to produce equol is tied to their (polysaccharide-rich) gut flora and their (plant protein and fibre-rich) diet that together stimulate the growth of intestinal bacteria [57,61], as intestinal bacteria dictate the metabolism of daidzein into equol. Once the isoflavones have been metabolized and absorbed, the organism can use them to produce an estrogenic activity. However, the efficiency of this activity is dictated by cell and plasma concentrations of bioavailable isoflavones. In humans, 60–90% of the circulating fraction of phytoestrogens are conjugated forms. These glucuronide conjugates are considered eliminatables and are inactive [62]. Following a 50 mg bolus of genistein or daidzein (less than 1 mg/kg body weight) administered to women, the plasma concentrations recovered were 1.26 ␮M genistein and 0.76 ␮M daidzein [59]. However, most pharmacokinetics studies work in terms of total plasma concentrations. The reported doses correspond to the sum of the conjugate and aglycone fractions of genistein and daidzein. Plasma concentrations reported as efficient are around the hundred-odd nM mark. At cell level, predicting phytoestrogen bioavailability is a complex task, as cellular concentrations of

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free genistein and daidzein are shaped by several parameters like bloodflow and how readily the compounds can penetrate the cell membrane. This complexity is further compounded by a chronic lack of data on cellular concentrations of these phytoestrogens in humans. A recent study by Guy et al. (2008) measured prostatic isoflavone concentrations in BPH patients given isoflavone supplements, and found lower prostatic cell concentrations than plasma concentrations [63]. 3.5.8. Analogies and differences between soy phytoestrogens and 17β-estradiol A property shared by phytoestrogens and E2 is that both exert estrogenic-like effects. This action likely stems from a structural similarity shared by these compounds [64] (Fig. 4). This structural similarity essentially revolves around their shared 2phenol-ring nucleus – without which they would be unable to bind to estrogen receptors (ERs). E2 is a steroid sex hormone that acts on various organs – including the brain – to regulate reproductive behavior patterns [65]. Like all sex hormones, E2 is derived from the conversion of cholesterol, but its direct precursor is testosterone. Testosterone is metabolized into E2 by aromatase or cytochrome P450. This aromatization process, which produces 75–90% of all serum E2 in men, occurs essentially in peripheral tissue – mainly in fat but also in minor amounts in skin, kidneys, bone and brain [66]. A small amount (15%) of serum E2 is synthesized in the testes and Sertoli cells. E2 – the main cyclically-secreted hormone in women from puberty through to menopause – has a deep-reaching influence on female physiology and behavior. It is responsible for reproductive organ growth and bone maturation [67]. Men only produce as much E2 as post-menopausal women (40 ␮g/jour), yet the amount produced is still crucial to male fertility [66]. Despite sharing structural similarity, phytoestrogens and E2 have very different affinities for the two ER isoforms. Several studies based on cell binding or proliferation tests have shown that phytoestrogens have stronger affinity for ER␤ whereas E2 has stronger affinity for ER␣ (Table 3) [68,69]. Furthermore, genistein has a demonstratedly stronger affinity for ER␤ than

Fig. 4. Schematic illustration of the structure of 17␤-estradiol, genistein and daidzein – the prominent soy phytoestrogens [70].


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Table 3 Estrogen receptor relative binding affinities of estradiol, genistein and daidzein. The binding affinity of estradiol was arbitrarily set to 100 [164]. Compounds

Estradiol Genistein Daidzein

Relative binding affinity ER␣

ER␤

100 4 0.1

100 87 0.5

daidzein [70]. Phytoestrogens, in contrast to E2, can also induce anti-estrogenic effects. This stems from their ability to modulate the transcriptional activity of ER to make them recruit certain co-factors that go unrecognized in E2 binding [71]. It could also explain why different estrogenic and/or anti-estrogenic effects are observed according to tissue and phytoestrogen under study. Furthermore, phytoestrogens – again in contrast to E2 – are also able to bind other nuclear receptors such as androgen receptors and progesterone receptors [72]. Despite the structural overlap with E2, there are basic cues, such as the conformational change in ER in response to phytoestrogen binding, that lend these compounds very different and ultimately antagonist actions compared to endogenous natural estrogen. However, a majority of studies on the antagonist effects observed in presence of phytoestrogens were led with very heavy doses not generally employed in clinical practice. 3.5.9. Mechanisms of action of soy phytoestrogens Genistein and daidzein are phytoestrogens capable of engaging in the regulation of a panel of genes. Like estrogens, they essentially act on gene regulation via two main pathways: a genomic pathway and a non-genomic pathway. The genomic effect of phytoestrogens relies on nuclear receptors like ERs. Once the phytoestrogens have bound to the ER, it dimerizes to acquire a high affinity for specific DNA-binding domains called “estrogen response elements” (EREs). These EREs located in the promoter region of target genes enable target-bound ERs to modulate the expression of target genes [70]. Genistein binding to the peroxisome proliferator-activated receptor (PPAR␥) to control lipid metabolism is thought to be one of the genomic pathways mobilized by phytoestrogens to exert their actions. PPAR is one of a superfamily of nuclear receptor proteins that function as transcription factors for genes involved in lipid catabolism [73,74]. The molecular mechanisms underpinning non-genomic effects involve growth factor phosphorylation or tyrosine kinase inhibition. It has been shown that phytoestrogens like genistein can inhibit tyrosine kinases by competitively binding to their ATP-binding site, which induces the formation of non-productive enzyme–substrate complexes. The inhibition of tyrosine kinases has the knock-on effect of inhibiting many of the signaling cascades involved in tumour cell proliferation [75,76]. Soy phytoestrogens can act via various different pathways. A majority of their biological actions appear to borrow the genomic pathway, but a non-negligible number operate by controlling other metabolic pathways, such as the tyrosine kinase pathway.

3.5.10. Effects of soy phytoestrogens on prostate cancer So why study the role of phytoestrogens in prostate carcinogenesis when prostate growth and development are regulated by testosterone – which is an androgen? One of the first reasons is that although the amount of estrogen found in men is very low, it nevertheless plays a non-negligible hormonal role in prostate gland development and may therefore also be involved in prostate tumour development or protection against prostate cancer. It has been shown that estrogen combined with dihydrotestosterone (DHT) is able to induce the abnormal growth of cancer cells in mice [75]. Estrogens can thus induce a protective effect against prostate cancer by inhibiting the proliferation of cancer cells – an action in which the key mediator is thought to be ER␤ [77]. The phytoestrogens genistein and daidzein are able to bind to ER␤ and mimic the action of the estrogens. This could partly explain the anti-cancer effects of these molecules and their pull as a focus for prostate pathology research. The other, much older reason stems from the lower incidence of prostate cancer among Asian men than Western men. According to a number of epidemiological studies, this incidence differential is explained by diet, chiefly the regular intake of soy phytoestrogens. 3.5.11. Epidemiology research The early 1990s saw a surge in studies in both Asian and Western men looking to highlight a putative protective role of soy phytoestrogens against prostate cancer. Earlier, in 1989, Severson et al. had led a first prospective study on a population of 8000 men of Japanese ancestry in Hawaii. This study found that high consumption of soy-based food (tofu over 5 times a week) was associated with a lower incidence of prostate cancer [78]. Another case-control study led in 12 Chinese cities by Lee et al. (1998) reported a correlation between soy consumption and low incidence of prostate cancer. Lee et al. also showed that in a low-cancer-risk population, a diet switch such as excessive consumption of high-fat food can lead to an increased risk for prostate cancer [79]. Epidemiological studies in Western-world countries where diets rarely include any phytoestrogen-containing products show that these compounds likely have a protective effect. A study by Jacobsen showed a correlation between high intake of soy milk and low incidence of prostate cancer in USA-based Adventists [80] – which are a standout group in the US population since they regularly eat soy phytoestrogen-rich food. Another study led on a multiethnic-background cohort (black, white, Japanese, and Chinese American) found that people eating soy-based food were at lower risk for prostate cancer, but the low numbers of people in each ethnic subpopulation made it impossible to highlight a significant between-group difference in incidence rates in terms of tumour pathology. Other epidemiological studies have also been led, and the majority converge on a reduced risk of incidence in men exposed to soy phytoestrogens [81,82]. These studies stress a protective role of phytoestrogens against prostate cancer. However, as the case-control or prospective studies are based on diet questionnaires, they are exposed to a number of biases that may skew the correlations targeted. That said, the correlation between low incidence of risk and soy intake is also confirmed by studies assaying serum soy phytoestrogen levels between Asian and




Western populations. The first such study, led back in 1993 by Adlercreutz et al., showed that plasma isoflavone levels were 7 to 110-fold higher in Japanese men than in Finnish men [83]. These high serum levels could partly explain the incidence differential between these two subpopulations. It has also been demonstrated that urinary excretion of genistein and daidzein is 3-to-4-fold lower in Japanese-American men than in native Japanese men, which is potentially explained by a lower consumption and much lower metabolism of isoflavones in Japanese-Americans than native Japanese [84].

3.5.12. Experimental studies An array of in vivo and in vitro studies have provided evidence for a possible protective role of soy phytoestrogens against prostate cancer. This protective action is thought to be mediated by an inhibition of cell proliferation, an induction of apoptosis, an inhibition of angiogenesis, and an anti-oxidant activity. Phytoestrogen compounds are thus thought to have an effect on the main mechanisms of cell biology. These actions are relayed by the genomic pathway – essentially the ER␤ pathway – and the non-genomic pathway – by acting directly on the signaling pathways [85]. Soy phytoestrogens appear to be involved in the regulation of a panel of genes. It is established that soy phytoestrogens can upregulate the expression of tumour suppressor genes in prostate cancer tumors. Likewise, oncogene expression was downregulated in prostatic cells after treatment with soy isoflavones [86–88]. However, these studies fail to show whether the regulatory process is linked to epigenetic mechanisms. The fact that phytoestrogens are involved in epigenetic regulation is only a recent discovery, with most studies on this issue dating to the 2000s. Refocusing on prostate cancer, Day et al. (2002) were the first to show a drop in DNA methylation in prostate cancerbearing mice after a 4-week genistein diet [89]. Another study led by Fang et al. (2005) was able to highlight the impact of phytoestrogens on the methylation patterns of a small panel of genes that had been methylated in prostate cancer cells. The authors had previously shown the reactivation of some methylation-silenced genes in cancer cells by epigallocatechin3-gallate from green tea. Working to the hypothesis that if this phenolic compound was able to reverse the DAN methylation in prostate cancer cells, then other polyphenolics could have similar activities, the authors went on to test other food-source phenolics – including soy phytoestrogens [90]. A handful of studies have been led by other teams attempting to understand the mechanisms involved in the soy phytoestrogen-induced reversal of epigenetic alterations, and they all point to DNA methylation by gene promoters or histone modifications. Recent studies have shown that genistein and daidzein may be involved in another epigenetic modification – microRNA (miRNA) regulation [91,92]. Epigenetic modifications downregulate the expression of many tumour suppressor genes and cause abnormal oncogene expression. The reversal of these mechanisms is thought to be one of the processes employed by soy phytoestrogens to induce a protective effect against prostate cancer. However, it will still

9

take a battery of studies to determine all the pathways involved in the various visibly protective effects of phytoestrogens. Genistein and daidzein are the main phytoestrogen compounds in soy, and these micronutrients could be heavily involved in the prevention of prostate cancer. This hypothesis is supported by the epidemiological data, which points to a 30fold-lower incidence of prostate cancer in Asian men who eat a lot of soy than in Western men who eat next to none. Soy phytoestrogens appear to be involved in the regulation of epigenetic mechanisms, such as the epigenetic regulation of miRNA genes. Rabiau et al. [93] led an in vitro study on 3 continuous prostate cancer cell lines (PC-3, DU145 and LNCaP) treated for 48 h with 40 ␮m genistein, 110 ␮m daidzein and 2 ␮m azacytidine (a demethylating agent). They determined the expression profile of a 377 miRNA panel using a TaqMan® Low Density Array. Out of the 377 miRNA tested, after treatment with genistein or daidzein, 180, 170 and 150 miRNAs were amplified with 2% variation in the triplicate in PC-3, DU145 and LNCaP cells, respectively. These miRNA expression variations in all three lines are equivalent to those observed in presence of the demethylating agent used, i.e. 5-azacytidine. The results suggest that the genistein and daidzein soy phytoestrogens used in the study regulated miRNAs by acting on miRNA methylation status. This study ultimately demonstrates a potential protective effect of genistein and daidzein in prostate cancer, where one of the mechanisms underpinning this putative potency is a reversal of epigenetic modifications – chiefly DNA methylation – in the prostate cancer cells. It also shows that although miRNA are fully-fledged epigenetic modifications, they are themselves regulated by epigenetic modifications like DNA methylation. 3.6. The other risk factors Among the other risk factors for prostate cancer, studies have singled out obesity [94]. A recent study found that smoking was associated with a higher incidence of prostate cancer in a specific subpopulation – a Chinese population carrying a particular polymorphism of the XPC (xeroderma pigmentosum, complementary group C) gene, in which the smokers were at higher risk for prostate cancer than the non-smokers [95]. Outside of genetic factors, there are epigenetic factors associated with risk for prostate cancer. These epigenetic modifications are mainly found in cases of sporadic cancer. These epigenetic alterations – chiefly DNA methylation, miRNA-mediated gene regulation, and histone modifications – lead to the inactivation of several genes considered as tumour suppressor genes. They thus play a role in carcinogenesis. 4. Epigenetic modifications in prostate cancer 4.1. DNA methylation and prostate cancer Epigenetic alterations in DNA methylation and histone modifications are associated with tumour initiation and progression. Altered DNA methylation patterns are essentially described in cases of sporadic prostate cancer. The key question is whether




these aberrant methylation events are the cause or consequence of tumorigenesis [96]. Working out from Knudson’s ‘two-hit’ hypothesis, DNA methylation can be considered the cause of tumorigenesis in sporadic cancers [97]. Under this two-hit hypothesis, the inactivation of tumour suppressor genes could be due to two successive somatic events that lead to the loss of heterozygosity of these genes. Heterozygosity, here, is where an allele is lost and/or replaced by a duplicate copy of the remaining allele. This means that if the first event inactivates an allele by methylation, the loss of heterozygosity will translate into the methylation of the second allele when the second event hits, resulting in the loss of expression of the gene. A more recent study claims it is difficult to confirm or disconfirm causality between DNA methylation and tumorigenesis [98]. Two major types of DNA methylation alterations have been observed in human – prostate cancer included: hypomethylation and hypermethylation of CpG islands. Hypomethylation is a non-specific process occurring in CpG islands throughout the genome. Hypermethylation occurs at specific gene regulation sites – the CpG islands on gene promoter regions – and results in a loss of expression of individual genes [99]. Hypomethylation is defined as the demethylation or normally methylated genes like sequence repeats, oncogenes. Hypomethylation breaks down into two categories: global hypomethylation, which is associated with a global genome-wide drop in 5-methylcytosine levels, and genomic hypomethylation, which refers to a more localized drop in methylated cytosine levels in a specific region of the genome, such as the promoter regions of proto-oncogenes [100]. The literature reports very few hypomethylated genes in prostate cancer, and the few genes reported are all either oncogenes or transposable elements (Table 4) [101–106]. DNA hypomethylation has also been described in other cancers, including breast cancer, bladder cancer and colon cancer [107,108]. and is also associated with other non-cancer diseases such as Alzheimer’s or Parkinson’s [109], [110] as well

as congenital heart defects. Global hypomethylation in mothers is associated with a risk of congenital heart defects in the child [111]. Although hypomethylation is a strong driver of prostatic carcinogenesis, hypermethylation has been the focal point of most research. DNA hypermethylation is the best-characterized epigenetic modification in human cancers – prostate cancer included. It is characterized by a methylation of the CpG islands in the promoters of tumour suppressor genes involved in various cell processes. The hypermethylation of tumour suppressor gene promoter sequences inhibits their transcription and thereby helps drive prostate carcinogenesis [112]. This is because the methylation of cytosine in the promoter regions prevents the binding of transcription factors and – as a knock-on effect – the transcription of target genes (Fig. 5). It has been demonstrated that these two aberrant methylation patterns are co-correlated mechanisms – the hypermethylation of certain genes precedes retrotransposon hypomethylation [101]. Gene hypermethylation kicks in very early, right from tumour initiation, and steadily continues throughout the process. An array of in vivo and in vitro studies has identified a fairly large set of hypermethylated genes in prostate cancer [113,114]. The best-researched genes include the genes involved in DNA repair, such as GSTP1 and MGMT, AR, and certain genes involved in cell cycle control, such as CDKIs and RASSF1. DNA hypermethylation is evidenced in all the tumour suppressor genes involved in various biological processes (Fig. 6). An in vitro study demonstrated highly recurrent hypermethylation patterns in tumour suppressor genes, followed by transcription factor genes and cell cycle genes [113]. The methylation rates of these genes in prostate cancer cells vary between studies, possibly according to technique employed and/or biological material used. Both in vivo and in vitro studies show heavy methylation of certain genes, including GSTP1 and APC, and there are reports that hypermethylation of these genes is

Table 4 List of genes reported as hypomethylated in prostate cancer. Definition of gene codes, chromosomal location, and description of the biological functions of each gene. References cited are those reporting hypomethylation of these genes in prostate cancer. Genes

Description

Chromosomal location

Role/Function

Bibliography

LINE-1 uPA

Retrotransposable element 1 Urokinase plasminogen activator Heparanase

22 10q24

[101] [102]

2p22

CAGE WNT5A

Cytochrome P450, family 1, subfamily B, polypeptide 1 Cancer/testis antigen Wingless-type MMTV integration site family, member 5A

CRIP1

Cysteine-rich protein 1

14q32

S100P

S100 calcium binding protein P

2q37

Retrotransposable element Involved in tumour invasion and metastasis Overexpression of the heparanase protein is heavily implicated in angiogenesis and tumour metastasis Involved in redox reactions Plays a role in pro-carcinogen activation Oncogene Involved in the intracellular signaling that modules the transcription of a large number of target genes. Acts as an oncogene Intracellular transporter of zinc proteins. Considered an oncogene Plays a role in the control of gene expression. Considered as an oncogene

HPSE

CYP1B1

4q21

6p24 3p21

[103]

[104] [105]

[106]




11

Fig. 5. Regulation of gene function by hypermethylation. The presence of methylated cytosines in the gene promoter region prevents transcription of the gene [122].

correlated to an increased risk of mortality in prostate cancer patients [115]. The methylation rates of other genes, like ASC and RASSF1, are reported to be highly correlated to increased risk of prostate cancer relapse, aggressivity and tumour progression [116–120]. The demonstrated correlation between rate of methylation of these genes and risk of relapse or mortality has prompted many teams to suggest using DNA hypermethylation as a diagnostic or prognostic biomarker of prostate cancer [121–125]. Although this hypothesis looks a promising target

Fig. 6. Schematic diagram illustrating how DNA methylation is involved in various cellular processes. DNA methylation regulates the expression of genes involved in biological processes such as cell apoptosis, cell cycle, and cell differentiation [118].

for ongoing and future research, other in-depth analyses are needed to determine whether clinical application is feasible. Gene hypermethylations have also been demonstrated in other non-prostate cancers, including breast cancer and colon cancer [126,127]. 4.2. miRNAs and prostate cancer miRNA-mediated gene regulation is an epigenetic modification associated with carcinogenesis [128]. Depending on the focal target gene, miRNA are considered as either oncogenes (oncomiR) or tumour suppressor genes [129,130]. Prostate cancer includes aberrant expression of miRNA – where oncomiR up-regulation correlates with tumour suppressor gene downregulation [131–133]. miRNA has been shown to induce a decrease in EZH2 gene expression in normal cells. EZH2 is polycomb-group (PcG) protein – a family of proteins associated with DNA methylation, histone methylation and, consequently, transcriptional silencing. EZH2 silencing may be one of the pathways of miRNA epigenetic regulation. The expression of this miRNA is downregulated in tumour cells, which would upregulate EZH2 expression and, consequently, increase DNA methylation in EZH2 target genes [134]. However, it is well established that in cancer settings, the miRNA is itself exposed to epigenetic modifications like DNA methylation [135,136]. It has been demonstrated in cancer in general, and specifically in prostate cancer, that hypermethylation of CpG islands located near miRNA or hypermethylation of miRNA genes is correlated




Fig. 7. Mechanisms potentially responsible for aberrant miRNA expression in prostate cancer: (1) DNA methylation; (2) gene rearrangements; (3) single nucleotide polymorphisms (SNPs); (4) increased Dicer activity; (5) the androgen–androgen receptor complex. (1), (2) and (3) downregulate the expression of miRNA. (2), (4) and (5) upregulate the expression of miRNA targets [137].

to downregulated target miRNA expression. miRNA is also governed by other mechanisms such as gene rearrangements or increased Dicer activity that could be responsible for the aberrant expression of oncomiRs or tumour suppressor gene miRNA in prostate cancer [137] (Fig. 7). 4.3. Histone modifications in prostate cancer Although DNA methylation has been widely studied in the prostate cancer literature, histone modifications have gone understudied. Nevertheless, in a prostate cancer background, research has found hypoacetylation of histones H3 and H4 in a number of genes [138,139]. Hypoacetylation (a drop in histone acetylation marks) is associated with chromatin condensation and inhibition of transcriptional regulation. The other histone modification seen in prostate cancer is histone methylation. Prostate cancer features increased H3K9 and H3K27 methylation, both of which are marks associated with inhibited gene transcription[138,140,141], and decreased H3K4 and H3K18 methylation, both of which are transcriptional activation marks [142,143]. Modified methylation or acetylation of these marks is often associated with DNA methylation in prostate cancer. 5. Conclusion Prostate cancer is one of the most common malignancies found in men the western hemisphere, which makes it cancer a very real public health issue. The disease generally hits over-50s men. Many factors are implicated in the development of prostate cancer, including genetic factors, ethnicity factors

and environmental factors. Looking at known genetic factors, family history of prostate cancer is a recognized risk factor for prostate cancer [144,145]. Men with prostate cancer in the family appear to have doubled the risk of developing the disease [146,147], and this familial-clustered form of prostate cancer is found in younger subjects (under-50s). There is genetic heterogeneity in the hereditary forms of prostate cancer, as a variety of genes on different loci have all been identified as prostate cancer-susceptibility genes [91,148]. Furthermore, mutations in genes predisposing for other cancers are also found in the familial forms of prostate cancer [10,11,149], whereas the sporadic forms (accounting for 90–95% of cases) essentially feature modified expression of tumour suppressor genes. This is a demonstrated ethnic disparity in the onset of prostate cancer. African-American men are at higher risk of developing prostate cancer than their Caucasian counterparts [150]. which the evidence suggests is tied to specific gene polymorphisms carried in this population [14,15]. The other risk factors associated with prostate cancer are largely environmental. Exposure to toxic agents – such as the agents found in certain herbicides – has been suggested as a risk factor for prostate cancer, although this association has only been demonstrated in the particular subpopulation of US Vietnam War veterans [151,152]. Farm workers occupationally exposed to pesticides have been shown to be at increased risk of developing prostate cancer [153,154], but – interestingly – this association was limited to North-American farm workers and did not extend to European farm workers [155]. However, there is debate over these results since another study failed to find a significant association between crop pesticide use and prostate cancer [156]. The literature also cites other risk factors such as




cigarette smoking or the nitrosamines used in rubber products [157–159]. Despite an array of epidemiological evidences, no study has yet been able to conclusively establish direct causality between these environmental factors and prostate cancer onset. The environmental factor that has risen to the top of the research agenda in the last few years is diet. The increasing focus on nutrition–cancer linkages has spotlighted fruit and vegetables as a rich source of micronutrients with possible cancer-preventive effects. Here, we have honed in on the potential effects of phytoestrogens on prostate cancer. Phytoestrogens are non-steroidal compounds found in dietary-relevant amounts only in soy, and evidence is accruing from epidemiological studies that soy consumption is inversely correlated to the incidence of certain cancers – prostate cancer included [160–163]. These soy phytoestrogens – genistein and daidzein being the best-researched so far – appear to act on the main mechanisms of cell biology and the main epigenetic modifications involved. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements Laurent Guy received grant funding from the French anticancer league [Ligue contre le Cancer – Auvergne-Region Committee] for 2012 and 2013. Aslihan Dagdemir funded by Protema Saglik Hizm.A.S. Istanbul, Turkey and Seher Karsli-Ceppioglu grant by The Scientific and Technology Research Council of Turkey (TUBITAK-2219). References [1] Belot A, Grosclaude P, Bossard N, Jougla E, Benhamou E, Delafosse P, et al. Cancer incidence and mortality in France over the period 1980-2005. Rev Epidemiol Sante Publique 2008;56(3):159–75. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893–917. [3] Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol 2012;61(6):1079–92. [4] Brawley OW. Prostate cancer epidemiology in the United States. World J Urol 2012;30(2):195–200. [5] Fromont G, Yacoub M, Valeri A, Mangin P, Vallancien G, Cancel-Tassin G, et al. Differential expression of genes related to androgen and estrogen metabolism in hereditary versus sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 2008;17(6):1505–9. [6] Xu J. Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am J Hum Genet 2000;66(3):945–57. [7] Berthon P, Valeri A, Cohen-Akenine A, Drelon E, Paiss T, Wohr G, et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet 1998;62(6):1416–24. [8] Cancel-Tassin G, Latil A, Valeri A, Mangin P, Fournier G, Berthon P, et al. PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Eur J Hum Genet 2001;9(2):135–42.

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