Aggressive Prostate Cancer Is Prevented in ERαKO Mice and Stimulated in ERβKO TRAMP Mice

Previous evidence suggests soy genistein may be protective against prostate cancer, but whether this protection involves an estrogen receptor (ER)-dependent mechanism is unknown. To test the hypothesis that phytoestrogens may act through ER alpha or ER beta to play a protective role against prostate cancer, we bred transgenic mice lacking functional ER alpha or ER beta with transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Dietary genistein reduced the incidence of cancer in ER wild-type (WT)/transgenic adenocarcinoma of mouse prostate mice but not in ER alpha knockout (KO) or ER beta KO mice. Cancer incidence was 70% in ERWT mice fed the control diet compared with 47% in ERWT mice fed low-dose genistein (300 mg/kg) and 32% on the high-dose genistein (750 mg/kg). Surprisingly, genistein only affected the well differentiated carcinoma (WDC) incidence but had no effect on poorly differentiated carcinoma (PDC). No dietary effects have been observed in either of the ERKO animals. We observed a very strong genotypic influence on PDC incidence, a protective effect in ER alpha KO (only 5% developed PDC), compared with 19% in the ERWT, and an increase in the incidence of PDC in ER beta KO mice to 41%. Interestingly, immunohistochemical analysis showed ER alpha expression changing from nonnuclear in WDC to nuclear in PDC, with little change in ER beta location or expression. In conclusion, genistein is able to inhibit WDC in the presence of both ERs, but the effect of estrogen signaling on PDC is dominant over any dietary treatment, suggesting that improved differential targeting of ER alpha vs. ER beta would result in prevention of advanced prostate cancer. (Endocrinology 153: 4160-4170, 2012)