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Aggressive prostate cancer is prevented in ERαKO mice and stimulated in ERβKO TRAMP mice - PubMed

Aggressive prostate cancer is prevented in ERαKO mice and stimulated in ERβKO TRAMP mice

Anna Slusarz et al. Endocrinology. 2012 Sep.

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.

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Figures

Fig. 1.
Fig. 1.

ERα immunostaining in TRAMP mice. Mice were euthanized at 5 months, and prostates were analyzed for ERα immunostaining. Normal prostates from non-TRAMP mice were stained as control. A, PIN lesion. B, WDC lesion. C, PDC lesion. D, Plot of IHC scores. n = 45, from studies 1 and 5–7 (see Supplemental Table 2). ERα expression decreases with cancer progression. In PDC tumors, even though quantitatively lower, the expression shifts from mainly nonnuclear to nuclear. Scale bar, 20 μm. Inset in A shows negative control with specific blocking peptide. *, P < 0.05.

Fig. 2.
Fig. 2.

ERβ immunostaining in TRAMP mice. Mice were euthanized at 5 months, and prostates were analyzed for ERβ immunostaining. Normal prostates from non-TRAMP mice were stained as control. A, PIN lesion. B, WDC lesion. C, PDC lesion. D, Plot of IHC scores. n = 49, from studies 1, 2, 6, and 7 (see Supplemental Table 2). ERβ expression did not significantly change with tumor progression. Scale bar, 20 μm. Inset in A shows negative control with specific blocking peptide.

Fig. 3.
Fig. 3.

AR immunostaining in TRAMP mice. Mice were euthanized at 5 months, and prostates were analyzed for AR immunostaining. Normal prostates from non-TRAMP mice were stained as control. A, PIN lesion. B, WDC lesion. C, PDC lesion. D, Plot of IHC scores. n = 49, from studies 1 and 5–7 (see Supplemental Table 2). There is a very significant reduction of AR expression in PDC tumors. Scale bar, 20 μm. Inset in A shows negative control without antibody. *, P < 0.05.

Fig. 4.
Fig. 4.

Stromal immunostaining in TRAMP mice. Mice were euthanized at 5 months, and prostate stroma was analyzed for AR (A), ERα (B), and ERβ (C) immunostaining. Relative immunostaining was noted for prostates with a weighted lesion stage. Normal prostates from non-TRAMP mice were stained as control. Error bars show

sd

. Statistical significance (P < 0.05) between different stages is noted with differing letters.

Fig. 5.
Fig. 5.

Mouse body and prostate weights from all studies combined. A, ERWT mice fed the high genistein diet and ERαKO mice fed the low genistein diet had significantly increased total body weight compared with those fed the casein diet. When combined as in B, there are no significant differences in prostate weights. When we applied a cut-off of 1.5 g for very large prostate, which were exclusively PDC, we obtained a more differentiated pattern for prostate weight above 1.5 g (C) and under 1.5 g (D).

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