Estrogen Action and Prostate Cancer

Jason L Nelles; Wen-Yang Hu; Gail S Prins

Disclosures

Expert Rev Endocrinol Metab. 2011;6(3):437-451. 

In This Article

Phytoestrogens & Prostate Health

In addition to their ability to influence testosterone levels and bone mineral homeostasis, it has been proposed that natural estrogens and dietary estrogen analogs may be protective against the development of prostate cancer, rather than simply being a treatment for prostate disease. This has resulted in extensive research into the anticancer properties of phytoestrogens, and in particular soy isoflavones such as genistein. The initial evidence for this was epidemiological, with the age-standardized incidence of prostate cancer in Japan, where soy consumption is high, being 12.6 per 100,000 men as compared with 119.9 in the USA.[185] However, among second- and later-generation Japanese populations living in the USA, the incidence of prostate cancer is much closer to that of the general US population, suggesting an environmental or dietary cause for the difference observed. Subsequent studies focusing on soy and its associated proteins investigated the dietary impact on the risk of prostate cancer, with a large meta-analysis suggesting that both fermented and nonfermented soy were protective against cancer, with odds ratios of 0.69 and 0.75, respectively.[186] While tofu was the only individual food showing a protective effect, the phytoestrogens genistein and daidzein were also associated with a lower risk of prostate cancer.

Further evidence of the protective effect of genistein can be gleaned from studies using rodent models and human cell lines. In two separate studies, Mentor-Marcel and colleagues investigated the effects of genistein on the progression of prostate cancer in the TRAMP mouse model of prostate cancer.[187,188] When dietary genistein was used to elevate mouse serum genistein to levels comparable to that of Asian men, the rate of poorly differentiated adenocarcinoma decreased in a dose-dependent manner,[187] while survival improved as a function of decreased tumor burden.[188] Recent studies using a rat hormonal carcinogenesis model have shown that a soy isoflavone mixture that includes genistein and diazein is able to protect against carcinogenesis in the dorsolateral and anterior prostate lobes.[189] In vitro studies revealed that genistein inhibited growth of two prostate cancer cell lines alone or in combination with selenium.[190] The treatment also induced apoptosis through caspase-dependent pathways, and reduced expression of matrix metalloproteinase 2, which has been associated with active invasion and metastases.

While the exact mechanisms of genistein's protective effects have not been elucidated, many current studies are focused on changes in DNA methylation and other mechanisms that alter gene and protein expression. The promoter CpG islands of many tumor-suppressor genes become methylated in several prostate cancer cell lines, resulting in silencing of their transcription. Treatment with genistein and other soy phytoestrogens resulted in demethylation of the glutathione-S-transferase P and epoxide hydrolase receptor B2 gene promoters, with parallel rises in their protein expression by immunohistochemistry.[69] This is significant since glutathione-S-transferase P, a π-class glutathione-S-transferase, is silenced by promoter hypermethylation in prostate basal cells and is one of the known early events in human carcinogenesis due to the loss of its protective antioxidant capacity.[191] A similar study in prostate cancer tissues as well as cell lines demonstrated that the tumor-suppressor B-cell translocation gene 3 is silenced in prostate cancer, with re-expression induced by demethylation with either genistein or 5-azacytidine.[70] An alternative proposed mechanism of action is through changes in histone rather than promoter modification. Several tumor-suppressor genes (PTEN, CYLD, p53, FOXO3a and SIRT1) were identified that are silenced in prostate cancer cell lines, but have unmethylated promoter regions. Expression of these tumor-suppressors was restored after treatment with genistein, and this was found to be associated with either methylation or deacetylation of histone H3-lysine 9.[71] Finally, there is ample evidence that genistein induces at least some of its changes through ER-mediated pathways, in particular ERβ, for which it has higher affinity. Apoptosis-inducing effects of genistein on T-cell leukemia cells can be blocked by the antiestrogen ICI,[192] and other observed effects of genistein appear to be blocked by silencing of the ERβ in gerbil neurons[193] or PC-3 prostate cancer cells.[194] As described previously, the ERβ-mediated effects of phytoestrogens may partly depend on specific ERβ gene polymorphisms.[147]

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