Aggressive prostate cancer is prevented in ER?KO mice and stimulated in ER?KO TRAMP mice.

ABSTRACT: 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? or ER? to play a protective role against prostate cancer, we bred transgenic mice lacking functional ER? or ER? 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? knockout (KO) or ER?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?KO (only 5% developed PDC), compared with 19% in the ERWT, and an increase in the incidence of PDC in ER?KO mice to 41%. Interestingly, immunohistochemical analysis showed ER? expression changing from nonnuclear in WDC to nuclear in PDC, with little change in ER? 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? vs. ER? would result in prevention of advanced prostate cancer.

SUBMITTER: Slusarz A 

PROVIDER: S-EPMC3423626 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature