Genistein chemoprevention of prostate cancer in TRAMP mice

Abstract

Epidemiological studies suggest an inverse association between soy intake and prostate cancer risk. Genistein, the predominant phytoestrogen in soy food, has been proposed as a potential chemopreventive agent due to its anti-estrogen and tyrosine kinase inhibitory effects. To determine the most effective period for genistein chemoprevention, the Transgenic adenocarcinoma mouse prostate (TRAMP) model was used. The treatments were 250 mg genistein/kg AIN-76A diet 1) prepubertally only, 2) in adulthood only or 3) through out life. Controls received AIN-76A diet. By 28 weeks of age, 100% TRAMP mice fed control diet developed prostatic intraepithelial neoplasia (PIN) or adenocarcinomas with 6%, 16%, 44% and 34% developing high grade PIN, well differentiated, moderately differentiated and poorly differentiated prostatic adenocarcinomas, respectively. Prepubertal only (1-35 days postpartum) and adult only genistein treatments (12-28 weeks) resulted in 6% and 29% decreases in poorly-differentiated cancerous lesions compared with controls, respectively. The most significant effect was seen in the TRAMP mice exposed to genistein throughout life (1-28 weeks) with a 50% decrease in poorly-differentiated cancerous lesions. In a separate experiment in castrated TRAMP mice, dietary genistein suppressed the development of advanced prostate cancer by 35% compared with controls. Of the tumors that developed in castrated TRAMP mice, 100% were poorly-differentiated in contrast to the 37% of noncastrated TRAMP mice that developed poorly-differentiated tumors. ICI 182,780 (ICI), genistein and estrogen down-regulated androgen receptor (AR), estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) in the prostates of C57BL/6 mice, and act independently of ER. Our data obtained in intact and castrated transgenic mice suggest that genistein may be a promising chemopreventive agent against androgen-dependent and independent prostate cancers.

Figure 1

Estrogen receptor expression in dorsolateral prostates of adult mice treated with one injection of vehicle (C), genistein (G) or estradiol benzoate (E) (with or without pretreatment with ICI 182,780 (I) thirty min prior to injection), and sacrificed 16 h later. ^a P < 0.001 compared to controls; ^b P < 0.001 compared to ICI 182,780 treatment; ^c P < 0.001 compared to estrogen or genistein treatments.

Figure 2

Progesterone receptor expression in dorsolateral prostates of adult mice treated with one injection of vehicle (C), genistein (G) or estradiol benzoate (E) (with or without pretreatment with ICI 182,780 (I) thirty min prior to injection), and sacrificed 16 h later. ^a P < 0.001 compared to control; ^b P < 0.001 compared to ICI; ^c P < 0.05 compared to estrogen treatment; ^d P < 0.05 compared to ICI treatment.

Figure 3

Androgen receptor expression in dorsolateral prostates of adult mice treated with one injection of vehicle (C), genistein (G) or estradiol benzoate (E) (with or without pretreatment with ICI 182,780 (I) thirty min prior to injection), and sacrificed 16 h later. ^a P < 0.001 compared to controls; ^b P < 0.001 compared to ICI; and ^c P < 0.05 compared to genistein treatment.