Diet is estimated to contribute to approximately 50% of all newly diagnosed breast cancers. As such, a search for dietary factors differentially consumed among populations with increased breast cancer risk (e.g., Caucasians) compared to those with low risk (e.g., Asians) has become a priority. One such dietary component, which is typical to the Asian but not the Caucasian diet, is soy. We review data relevant to attempts to determine whether soy, and more specifically genistein, is a dietary component that may help to explain the dramatic disparity in breast cancer risk among these populations. Key words: antiproliferative effects, breast cancer, estrogenic effects, genistein. Environ Health Perspect 108:701-708 (2000). [Online 23 June 2000]
Epidemiologic data indicate a great disparity between breast cancer risks in Western and Eastern countries. Historically, the risk of American women developing breast cancer has been as high as 7 times that of Asian women (1). Today the disparity in risk is similarly significant, although the difference in incidence between Western and Eastern countries has narrowed slightly. For example, one in eight white women in the United States can expect to develop breast cancer in her lifetime; this risk is roughly 5-fold less in Japanese and Chinese women residing in Asia (2). However, extensive migration studies indicate that Asian women who immigrate to the United States and adopt a Western lifestyle develop risk comparable to Caucasian women within two generations (3,4). These studies provide strong evidence in support of other epidemiologic studies showing that 5-10% of breast cancer cases are estimated to be attributable to inherited factors, and thus [is greater than] 90% of newly diagnosed breast cancers may be caused by unspecified factors probably related to lifestyle. Ziegler et al. (5) investigated the link between age of immigration to the United States and increased breast cancer risk in Chinese, Japanese, and Filipino women. The authors found a strong correlation between early age of immigration ([is less than] 35 years of age) and a marked increase in breast cancer risk (5). In fact, Asian women born in America, compared to their counterparts born in the East, had a 60% higher risk of breast cancer. Additionally, in all three ethnic groups, immigrants living in the United States for more than a decade had a significantly greater risk than more recent immigrants (5).
It is clear from both epidemiologic and clinical data that exposure to estrogens has significant influences on breast cancer development. Estrogens induce the proliferation of normal and malignant mammary cells, and are thus linked to breast cancer promotion and progression. Interestingly, a number of reports indicate that Asian women living in Asia have up to roughly 40% lower serum estrogen levels than Caucasian women living in the United States or Britain (6,7). Based on these data, it is increasingly clear that the protective effect seen in Asian countries does not correlate with genetic influences, but rather, with environmental and lifestyle factors. Thus, it has long been the goal of innumerable scientists to isolate those factors that may be responsible for the dramatic disparity in breast cancer risk between Caucasian and Asian women.
Diet is estimated to contribute to up to 50% of all newly diagnosed breast cancer cases (8,9). One particular class of dietary compounds that has received much attention, based on their high concentration in potentially protective foods and their reported antiproliferative effects, is phytoestrogens. Consumption of phytoestrogens, particularly soy products, as well as legumes, is higher in Asia than in the Western world (10). Soybased diets are high in genistein (4,5,7-trihydroxyisoflavone), which has been widely studied for its potential anticancer properties. The exact mechanism by which genistein may exert its antitumorigenic effects is not clearly understood; however, it is a specific and potent inhibitor of both protein tyrosine kinases and topoisomerase II (11,12). Furthermore, genistein is able to inhibit angiogenesis and metastasis in some tumor models and to selectively reverse multidrug resistance protein-associated multidrug resistance in in vitro studies (13-15). Recently, genistein's ability to inhibit the cytochrome P450 enzyme CYP1A1 has been described (16). The inhibition of CYP1A1 may lead to a reduction in the production of DNA-damaging carcinogen metabolites and may be one mechanism by which genistein can protect against carcinogenesis (16). Given reports of its antiproliferative abilities, genistein appears to be a potentially powerful weapon in the breast cancer prevention and treatment arsenal. A recent review by Barnes (17) discussed the possible protective role of genistein in breast cancer, However, at closer look genistein may not be all it is touted to be.
Estrogenic Effects of Genistein
The phytoestrogen genistein is present naturally as several [Beta]-glucosides, which are metabolized by intestinal microflora to genistein (15). Genistein, a planar molecule with an aromatic A ring, has a chemical structure similar to steroidal estrogens, and its ability to behave as an estrogen in various tissues has been widely described. Observations of phytoestrogens' estrogenic properties date back to the 1950s, when it was discovered that the diadezan metabolite equol was the compound responsible for reduced reproductive capacity in sheep grazing on clover. Subsequently, countless studies have been conducted to characterize the hormonal effects of phytoestrogens including genistein's estrogenic and presumed antiestrogenic properties.
Genistein has significant estrogenic properties in both in vitro and in vivo models (Table 1). Genistein binds to the estrogen receptor (ER), although its binding affinity is several-fold weaker than that of estradiol (30). Genistein can also activate a number of estrogen-responsive genes in vitro, including pS2 and c-fos (18,31). Furthermore, when administered at low doses, genistein stimulates the growth of ER-positive (ER+) breast cancer cells (18-20). Findings in other tissue systems support the estrogenicity of genistein. For example, genistein is uterotrophic in a variety of species, resulting in impaired reproductive activity and increases in uterine wet weights (21,25,26). It is important to note that some studies have failed to see any effect of genistein on the uterus, including alterations in wet weight (32,33). Furthermore, findings with coumestrol, a more estrogenic phytoestrogen than genistein, indicate that although coumestrol increases uterine wet weights, it does not increase uterine DNA content or alter other indicators of more true estrogenic activity (34). Thus, an increase in uterine wet weight alone does not necessarily indicate that genistein has estrogenic properties.
Table 1. Estrogenic effects of genistein.
Observation Reference Inhibition of CYP1A1 (16) Stimulation of ER+ human breast (18-20) cancer cells in vitro Stimulation of human ER+ breast (18) cancer cells in vivo Stimulation of rodent mammary gland (18,21,22) Stimulation of human breast (23,24) Stimulation of reproductive tissues (21,25,26) Estrogenic effects on bone, (27-29) cardiovascular system, and lipid profiles
In addition to directly binding to the ER, genistein may indirectly affect estrogenicity through inhibition of the cytochrome P450 enzyme CYP1A1. Ir has recently been shown that: genistein is a noncompetitive inhibitor of the CYP1A1 enzyme, which apart from playing a role in the metabolism of carcinogens, is responsible for the metabolic degradation of 17[Beta]-estradiol. Thus, it is possible that genistein-mediated inhibition of estradiol degradation could result in higher levels of circulating estradiol and thus elevated ER activity (16).
Genistein has estrogenic effects on the hypothalamic/pituitary axis in ovariectomized Sprague-Dawley rats (21). Human studies indicate that high soy intake can disrupt the hypothalamic/pituitary/gonadal axis in premenopausal women similar to that seen in animal models (23,35). This perturbation is not seen in postmenopausal women (36),suggesting a differential effect of soy/genistein on pre- and postmenopausal women. Finally, genistein may exert beneficial effects on bone, cardiovasculature, and lipid profiles, all of which are effects characteristic of estrogen (27-29). Taken together, these studies indicate that genistein can behave as an estrogen and can mediate mitogenic effects via the ER.
Estrogens have long been identified as important mitogens in the breast and thus are associated with an increase in breast cancer risk. This is evidenced by the link between reproductive factors, including ages of first menarche, first pregnancy, and menopause, and breast cancer risk (37). This is further supported by studies showing that elevated concentrations of estrogens in serum and urine are associated with increased postmenopausal breast cancer risk (38,39). Additionally, estrogens induce mitogenic effects in both in vitro and in vivo models of breast cancer (40). The role of estrogen in this disease is supported by the fact that removal of ovarian estrogens by bilateral ovariectomy (41) or use of tamoxifen (which blocks ER in the mammary gland) (42) significantly reduces breast cancer risk. Because estrogen exposure presumably increases breast cancer risk, evidence showing that genistein acts in an estrogenic fashion is puzzling in light of the in vitro reports of genistein as an anticancer agent. To address studies that demonstrate the protective effects of genistein in in vitro and in vivo breast cancer models, it is important to determine whether genistein has antiestrogenic properties as well.
Possible Antiestrogenic Effects of Genistein
Genistein does not always induce proliferation of ER cells. For example, in some studies genistein exhibits an antiproliferative effect in mammary and uterine tissues (19,43,44). Thus, these data could be interpreted to indicate that genistein is …