Phytoestrogens and Breast Cancer: Should French Recommendations Evolve?

1. Introduction

Breast cancer (BC) is the second most common cancer in the world and the most frequently diagnosed in females. There are about 2.3 million new cases and more than 680,000 deaths each year [1].After the initial treatment, women may experience a recurrence of the disease. Many factors may influence the risk of relapse. The characteristics of the cancer are the main factors that influence the risk of recurrence. Tumors of high grade, large size, and axillary nodal involvement have been shown to increase the risk of locoregional recurrence or metastasis. Women with a pre-menopausal diagnosis of BC have a greater risk of recurrence [2]. The tumor characteristics (high grade, high tumor size, and nodal involvement) are also associated with a higher risk of death and BC recurrence. Conversely, those risks are lower for patients with estrogen- or progesterone-receptor-positive tumors than in estrogen- or progesterone-receptor-negative ones. Women affected by this type of cancer are treated by hormonotherapy most of the time. This treatment is used to reduce the risk of relapse. Lifestyle factors might also influence the risk of recurrence and death after BC diagnosis. Excess weight is associated with both an increased risk of cancer and a higher risk of recurrence and death. Similar findings have been reported for both alcohol and tobacco use [3].The BC incidence rate is significantly higher in Western countries than in East and Southeast Asia [1]. One assumption put forward to explain this is the difference in lifestyle and diet, such as the high consumption of soy products in East Asia, associated with increased intake of phytoestrogens (Japan and China) [4].Due to their structural similarity with 17β-estradiol, phytoestrogens can bind to estrogen receptors (ER) and exert estrogenic effects. Indeed, they are selective ER modulators (SERM). That means they have a preferential selectivity for ERβ compared to Erα, while the mammary gland mainly contains Erα [5]. The repartition of these subtypes varies according to the types of tissues, which could influence the cellular response to different phytoestrogens (Table 1). Thus, ERα activation in mammary tissue enhances cell proliferation, which may contribute to the development of ER-dependent breast tumors. ERβ activation plays a role in counteracting ERα-mediated cell proliferation [6,7].Moreover, phytoestrogens also exert non-estrogenic effects. In vitro, genistein has epigenetic effects that may influence the regulation of cell proliferation and differentiation. This mechanism may affect BC development. Genistein has an inhibitive effect of protein kinase that might prevent the development of breast tumor cells [4].Phytoestrogens are nonsteroidal naturally occurring plant compounds. Five major classes of phytoestrogens have been described according to their chemical structures. Most of them are polyphenols, among which, besides isoflavonoids, some lignans, coumestans, (prenylated) flavonoids, and stilbenes were described as phytoestrogens. Some of them are found in cultivated edible or medicinal plants [6,8,9].Soybean (Glycine max (L.) Merr.) is a food plant rich in isoflavones. Isoflavones are also found in beans, chickpeas, hops, red clover, kudzu, and lentils. The main molecules of this group are genistein (1), daidzein (2), and glycetin (8), which account for 50%, 40%, and 10%, respectively, of the total soybean isoflavone content [7]. Soy-derived products are the only common foods that contain relevant amounts of isoflavones. Naturally, in plants, most isoflavones are glycoside derivatives (e.g., genistein 7-glucoside (1′)). This means the isoflavone part, called aglycone, is bound to a sugar via a glycosidic bond. Isoflavone glycosides do not exert any estrogenic effect, while isoflavone aglycones are biologically active. The proportion of these two forms, i.e., isoflavone aglycones or glycosides, varies among different kind of foods. For soy foods, it mainly depends on the processing conditions of soybeans. For example, fermented soy foods contain higher levels of free aglycones than other soy-based foods. After isoflavone ingestion, intestinal micro-organisms and enzymes metabolize these compounds in bioactive aglycones such as 12 and 8 (Table 2) [10].Flaxseed (Linum usitatissimum L.) is the richest sources of lignans (60–300 mg of SDG/100 g). In the seed coat, precursors such as the aglycon secoisolariciresinol (SECO, (3)) or the glycoside secoisolariciresinol diglucoside (SDG, (4)) are present. After ingestion, such lignans are metabolized by the gut microbiota into enterolignans. Like soy isoflavones, the latter are known to exert both estrogenic and non-estrogenic effects. They represent the main dietary intake of phytoestrogens in Western countries. They are also found in sesame seeds (Sesamum indicum L.) [12,13]. Hop (Humulus lupulus L.) is also a plant known for its hormonal effects. Its main active compound is a flavonoid, i.e., 8-prenylnaringenin (8-PN, (5)). Consequently, it is found in beer as well. In contrast with soy isoflavones, 8-PN has a higher affinity for Erα than Erβ [14]. Alfalfa (Medicago sativa L.) and clover (Trifolium spp.) are coumestan-rich plants [13] Like soy, red clover (Triofolium pratense L.) contains isoflavones. The dominant ones are biochanin A (6) and formononetin (7), which is metabolized in daidzein. It also contains genistein and daidzein, but in lower quantities compared to soy (Figure 1) [15].These foods are part of the traditional diet of East Asia. For this reason, isoflavone intake is significantly higher in this part of the world than in Western countries. For example, in Europe, the overall food intake of isoflavones is about 1 mg per day [16], while in Japan, the traditional diet provides 25 to 50 mg of isoflavones per day [17].In addition to dietary soy, food supplements containing phytoestrogens or plants known to have estrogenic effects are widely marketed to relieve hot flashes usually associated with menopausal disorders as an alternative to hormone replacement therapy. Some examples of dietary supplements containing phytoestrogens available for sale in pharmacies in France are shown in Table 3. These dietary supplements contain various numbers of active compounds, but some do not give precise information on the phytoestrogen dose in their extracts. For those containing soy, information on dosage allows the comparison between studies of the intake from dietary supplements with food intake. None of these food supplements are recommended by the manufacturers for use in women with a personal or family history of BC.Due to their estrogenic effects, phytoestrogens are handled with caution by the health scientific community from given countries [13] and can cause apprehension, especially for people with a family history of BC. However, in view of the epidemiological data in Asia, it seems reasonable to assume that soy may protect from developing BC. Since the 1990s, many studies have sought to show the link between soy isoflavone consumption and the development of BC. In 2022, the meta-analysis of Boutas et al. concludes that the consumption of soy isoflavones can reduce the risk of BC both in pre- and post-menopausal women [25].Several in vitro and in vivo studies showed that soy isoflavone aglycones may exert effects that could increase cancer cell development. Some studies on mice models showed that genistein induces MCF-7 cells proliferation in a dose-dependent way. Genistein also induced proliferation of MCF-7 in vitro. The concentration of genistein used in those studies imitated human exposure to dietary isoflavones. Similar results concerning daidzein were found in mice models and in vitro (MCF-7 cells). In one study, genistein specifically triggered the growth in ER+ cells (T47D and MCF-7) but did not impact growth in ER cells. Therefore, daidzein and genistein tumor-promoting effects seem to proceed via ER [26]. Yet, other studies showed beneficial effects of isoflavone aglycones on BC cells and even an anti-cancer treatment perspective. In mice, genistein was able to inhibit cellular matrix metalloproteases (MMP) which are involved in tumor cell migration, potentially alleviating metastasis. Daidzein and genistein can induce apoptosis, including BRCA (breast cancer gene) mutant cancer cells. They also inhibit cytokines and protein kinases. It appears that genistein promotes its anticancer effects via estrogen-independent signaling pathways. Indeed, many genistein properties proceed through its regulation of various genes. Genistein is found to inhibit angiogenesis by reducing circulating levels of VEGF (vascular endothelial growth factor) and decreasing microvascular density [27].Nevertheless, these in vitro and in vivo data do not allow extrapolating the physiological effects of isoflavones in humans. Indeed, in vitro concentrations are higher than those obtained in vivo, as rodents have plasma levels of genistein aglycone higher than that of humans. These differences between species can be explained by differences in isoflavone metabolism. Indeed, humans have a higher capacity of glucuronidation of steroid-like molecules in the intestine and liver than rats and mice. This allows to maintain unconjugated isoflavones (biologically active form) at relatively low concentrations [28]. Furthermore, estrogen concentration in the breast tissue is much lower than the circulating level [29]. It is therefore more interesting to rely on epidemiological studies.Such epidemiologic studies were conducted to determine whether there was a protective role of soy isoflavones against BC development. Results from these studies were highly variable. Some found an association between soy isoflavones and a reduction in BC risk, while others did not manage to show this association. However, in general, researchers did not seem to find adverse effects of soy consumption on BC development. In a recent meta-analysis including 16 prospective cohort studies, Zhao et al. found that a high or moderate isoflavone intake, compared to a low one, was not associated with BC risk, whereas a high soy food intake lowers BC risk compared to low soy consumption. Consequently, the mechanism of the preventive role remains unclear [4]. However, this work compared the highest soy isoflavone intake subgroups with the lowest ones from many studies. Not all values were given, and they varied greatly from one study to another. It is therefore difficult to interpret these results. In a meta-analysis of 18 studies, Okenkule et al. assessed that a higher soy intake leads to a reduced risk of BC. More precisely, this association was stronger for ER-negative breast tumors. In post-menopausal women, the study indicated that higher soy consumption reduced this risk, regardless of ethnicity, i.e., in Asian women as well as in other populations [30].Due to the estrogenic effects of soy isoflavones, one can wonder if the menopausal status could influence the association between soy intake and BC risk. Findings of these studies on the subject were inconsistent and contradictory. In 2014, Chen et al. conducted a meta-analysis to explore the association between soy isoflavone intake and BC risk for pre- and post-menopausal women. They included 30 studies about pre-menopausal women and 31 about post-menopausal women. In pre-menopausal women, soy isoflavone intake seems to be associated with a reduced BC risk. However, when looking more closely, this protective effect was only found in Asian studies versus Western studies. In post-menopausal women, the highest intake of soy isoflavones appeared to reduce BC risk by about 25% compared to the lowest consumption, this association was weaker in Western than in Asian countries [31]. It is important to point out that most of the studies which found an association between soy intake and a decreased risk of BC mostly refer to Asian and not Western populations. This reality could be largely attributed to the difference in the amount of soy consumed in these populations.A dose–response meta-analysis was conducted on more than 300,000 women to show the impact of soy food intake on BC risk. In this study, the mean value of usual soy isoflavone (aglycone or glycosylated form not specified) intake was 9.4 mg per day, which is equivalent to about 7.5 g of soybeans. Overall, no association between soy intake and BC risk was observed. However, when the studies were stratified by group depending on soy consumption, a decreased risk of BC was found in women, with the highest isoflavone intake (≥40 mg/day) in studies with a global high intake. On the contrary, studies with a global low or moderate soy isoflavone intake found no relation between soy isoflavones and BC risk. Moreover, the meta-analysis did not show any influence of menopausal status on the results. Finally, they assessed that each 10 mg of isoflavones per day was associated with a reduction of 3% of BC risk [32].In addition to the difference in soy consumption, other factors could explain the stronger benefits on BC risk in Asia than in Western countries. Because soy is part of the traditional diet in East Asia, women are exposed to it from an early age, which seems to have a greater protective effect against BC [33].In addition, it is unclear whether the same effect in BC risk associated with high soy intake is also applicable to family BC (5–10% of BC cases). In the Korean Hereditary BC Study, Ko et al. studied the impact of soy consumption on BRCA mutation carriers, which represent 25 to 40% of hereditary BC cases. They found that soy product consumption is associated with a lower BC risk in BRCA mutation carriers than in non-carrier family members. This association was stronger for carriers of the BRCA-2 mutation than for the BRCA-1 mutation [34].A recent study on 76,000 French women over 50 years old examined the relation between the consumption of soy supplements and the risk of BC. Food supplements that were consumed by women contained between 3.75 mg and 37.5 mg of soy isoflavone (glucoside form) per tablet (daily dose not specified). The total follow-up was 11 years. Overall, the study did not find a link between the use of soy supplements and the overall risk of BC. For current users of soy dietary supplements, the results showed a lower risk of ER+ BC. However, they found a higher risk of ER− BC for the current users. This association is stronger for women with a history of BC in first-degree relatives or over 5 years after menopause. The study did not find an association between a past use of soy supplements and BC risk compared with use, whatever the tumors’ ER status. Despite this, some of the authors’ findings led them to advise women with a family history of BC against taking soy supplements based on the precautionary principle [35].In a 2-year clinical trial, about 400 healthy menopausal women received a daily supplementation of soy isoflavone aglycones in the form of tablets (80 or 120 mg/day), which represented 1 to 4 times a high soy food consumption. This trial study could not conclude that soy isoflavone intake is associated with a decrease in BC risk. However, results were reassuring on the safety of isoflavones for menopausal women. Indeed, the 2-year supplementation did not increase participants’ breast density (which is a risk factor of BC), and no major adverse effects occurred [36].Based on scientific data at a given moment, various organizations have issued scientific recommendations and opinions regarding soy consumption and the risk of BC development and recurrence.In France, in 2005, AFSSAPS (Agence française de sécurité sanitaire des produits de santé), i.e., the organization that preceded the current ANSM (Agence Nationale de Sécurité du Médicament), published the report Sécurité et bénéfices des phyto-estrogènes apportés par l′alimentation—Recommandations, which contained guidelines about phytoestrogen intake. According to this report, isoflavone-rich foods such as soy foods can be consumed without excess as part of a varied and balanced diet. It is recommended not to exceed 1 mg/kg/day of isoflavones (aglycone equivalents) in food and from dietary supplements. Moreover, particular attention should be applied to pregnant women, post-menopausal women, and those with a personal or family history of cancer. In 2005, according to these experts, the risk of increased tumor cell proliferation could not be excluded. Thus, health authorities recommended specific labeling on dietary supplements containing phytoestrogens (including soy) or fortified foods: “not recommended for women with a personal or family history of BC” [13].Similarly, in 2015, the European Food Safety Authority (EFSA) published a scientific opinion about the safety of isoflavones from food supplements in menopausal women. Due to limited information, “the Panel did not conclude on the risk of estrogenic isoflavone-based food-supplements in postmenopausal women with a current diagnosis or history of estrogen-dependent cancer”. Furthermore, this assessment did not manage to derive a single health-based guidance value or a safe intake level for food supplements containing isoflavones. The EFSA considers that it is necessary to harmonize the way in which the quantity of isoflavones is presented in food supplement labels [16].In a different way, in 2012, the American Cancer society concluded in the Nutrition and Physical Activity Guidelines for Cancer Survivors that “current evidence suggest no adverse effects on recurrence or survival from consuming soy and soy foods” for BC survivors [37]. The American Institute for Cancer Research even advises to regularly eat soy. They reported that research results differ on whether soy foods are likely to reduce cancer risk, depending on various factors. They added that consistent findings show no increased risk of recurrence or mortality for BC survivors who consume soy foods. They also suggested “greater overall survival and decreased recurrence, among women a year or more after diagnosis who include moderate amounts of soy” [38].In the United Kingdom, the National Health Service and Cancer Research UK do not give specific recommendations about soy consumption for BC survivors, but they assess that soy may have a weak beneficial effect on BC risk. The NHS mentions that soy intake does not seem to have an impact on BC recurrence [39].No specific recommendations about soy intake and BC were found for China and Japan. However, soy-based foods are staple foods in the traditional Japanese diet and are commonly consumed in China. The dietary guidelines of these two countries advise Chinese and Japanese residents to eat soy foods daily [40].The objective of this review consists of analyzing the current literature in order to determine whether it is justified to advise avoiding soy in dietary supplements and/or food in women with a history of BC. Thus, we reviewed studies on the impact of soy intake regarding the mortality and relapse of women with BC.

— Update: 06-01-2023 — cohaitungchi.com found an additional article Phytoestrogens and prevention of breast cancer: The contentious debate from the website www.ncbi.nlm.nih.gov for the keyword phytoestrogens and breast cancer 2021.

EPIGENETIC MODULATION BY PHYTOESTROGENS

Over the last decade there has been an explosion in the number of studies concerning epigenetic changes and the development and progression of breast cancer[61] and not surprisingly these have included studies on the ability of phytoestrogens to alter the epigenome which could be useful in the prevention of cancer[61-63]. In fact studies have indicated that early childhood exposure to phytoestrogens could protect against breast cancer in later life[62] and references therein and this could involve epigenetic events (Figure ​(Figure2).2). Epigenetic changes are defined as heritable changes in gene expression which do not involve mutations of DNA nucleotide sequences. They include DNA methylation, histone acetylation and microRNA’s (miRNAs).

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DNA methylation occurs on cytosine in the cytosine-phosphate-guanine (CpG) dinucleotide sequence of genomic DNA, a reaction catalysed by DNA methyl transferases (DNMTs). CpG dinucleotide rich regions (known as CpG islands) are found in the promoter region of approximately 60% of all human genes and, whilst most CpG islands are unmethylated in normal cells, they become hypermethylated in cancerous cells leading to gene suppression, including the tumour-suppressing genes[61]. Along with DNMTs are the methyl-CpG-binding domain family of proteins which bind to a methylated gene and can inhibit transcriptional activity by altering chromatin structure. Chromatin structure can also be modified by histone acetylation which is catalysed by histone acetylase (HAT) and results in a more open structure of chromatin allowing access for transcription factors to DNA. The reverse occurs when histone proteins become deacetylated and this reaction is catalysed by histone deacetylases (HDACs). Histones may also be methylated by histone methyl transferases (HMT’s) and generally methylation causes gene transcription to be switched off. The most recent participant of the epigenetic field are the miRNAs, small non-coding RNAs that inhibit protein expression of target genes by binding to the 3’-untranslated region of mRNA causing degradation or inhibition of mRNA of the target gene[61,62] and references therein.

The most widely studied dietary components in relation to epigenetic changes are the tea polyphenols, epicatechins and epigallocatechins (EGCCs), the isoflavones, genistein and diadzein, resveratrol and curcumin and all have been well reviewed recently[63-66]. Relatively few studies have been directed towards epigenetic changes in breast cancer models and results have been inconclusive[61,62].

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Recent studies have shown that 20-40 µmol/L genistein stimulated expression of the tumour suppressing genes, p21WAF1 and p16INK4a, in breast cancer cells and that this was associated with a small reduction in the activity of HDACs but a large increase in the activity of HMTs[67]. The same group also showed that genistein can reactivate ERα expression in ER-ve breast cancer cells and that this effect was associated with increased markers of histone acetylation in the ERα promoter region and decreased activity of HDAC and DNMT[68]. Another study showed that µmol/L doses of genistein and diadzein “might reverse” DNA hypermethylation in breast cancer cells thus restoring expression of the oncosuppressor genes BRCA1 and BRCA2[69]. In biopsies of human breast tissue specific DNMT transcripts were increased in cells taken from the tumourous tissue compared to adjacent normal breast tissue and parallel studies showed that treatment of breast cancer cells lines with genistein, resveratrol, curcumin and EGCC also reduced the mRNA of the same DNMTs[70]. Whilst all these studies have been performed acutely with high doses of single phytoestrogens, we showed that long-term treatment with 10 nmol/L genistein down-regulated the expression of acetylated histone3, cyclin D1 and procaspase 9 and reduced the growth promoting effects of E2 and epidermal growth factor[71].

It is clear that both nutrition and exposure to phytoestrogens and other phytochemicals can have dramatic effects on epigenetic events and that these may become heritable through transgenerational mechanisms. Thus their impact on both disease and the health of future generations needs to be carefully considered.

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