Aggressive Prostate Cancer Is Prevented in ERαKO Mice and Stimulated in ERβKO 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 ERα or ERβ to play a protective role against prostate cancer, we bred transgenic mice lacking functional ERα or ERβ 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 ERα knockout (KO) or ERβKO 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 ERαKO (only 5% developed PDC), compared with 19% in the ERWT, and an increase in the incidence of PDC in ERβKO mice to 41%. Interestingly, immunohistochemical analysis showed ERα expression changing from nonnuclear in WDC to nuclear in PDC, with little change in ERβ 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 ERα vs. ERβ would result in prevention of advanced prostate cancer.

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…A similar remarkable effect of ERb agonists has been observed in the TRAMP mouse (transgenic mouse model for prostate cancer; Gingrich et al 1996). In this mouse model of prostate cancer, dietary genistein, is an ERbdependent pathway, reduced the incidence of prostate cancer and the severity of the invasive cancer was increased in ERb K/K mice (Slusarz et al 2012). One other confounding factor occurring in prostate cancer is the expression of the ERb splice variant ERb2.…”

The Role of Estrogen Receptor β in Prostate Cancer

“…Mice with PCa lacking ERα or ERβ treated with phytoestrogens showed that cancer did not progress in ERαKO mice whereas ERβΚΟ mice presented an increasing incidence of poorly differentiated carcinoma (Gleason scores 4 and 5) (78). Re-expression of ERβ via phytoestrogens elicited antiandrogenic effects, including downregulation of AR and its coactivators (79).…”

Deletion ofp21/Cdkn1aconfers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

“…20,23 The function of p53 and Rb is abrogated by SV-40 large T antigen; as a result, TRAMP male mice develop spontaneous progressive stages of PCa with time from early lesions of prostatic intraepithelial neoplasia (PIN) to late stage adenocarcinoma. 20,23 Furthermore, this PCa model has been also crossed with other genetically manipulated mice so as to generate bigenic mice, [28][29][30][31] which are employed to study the role of specific molecules in PCa progression. The changing patterns of CDKs and cyclins have been also well characterized during the progression of PCa in TRAMP model; 32 notably, we have reported the increased expression of p21 protein in TRAMP prostate with advanced stage of the disease.…”