Abstract 956: Targeting prostate cancer chemoprevention via the androgen receptor in a preclinical mouse model

Abstract

Abstract Prostate cancer is strongly associated with increasing age, with about 96 % of the cases occurring in men over 60 years of age. The high incidence and late age of onset make prostate cancer an ideal target for chemoprevention strategies as even a modest delay in carcinogenesis would significantly reduce the incidence of the disease. Chlormadinone acetate (CA) is one of the steroidal anti-androgen agents used in combined androgen blockade therapy as well as monotherapy for prostate cancer in Japan. However, no reports have been published for the chemopreventive potential of CA. We evaluated the efficacy of low-dose administration of CA to prevent or suppress prostate cancer using our PTEN conditional gene targeting mouse model. Six-week-old mice were injected subcutaneously with CA (50 mg/kg 3X/week) until the age of 15 or 20 weeks. The genitourinary tracts (GUTs), consisting of the prostate, urethra, bladder, seminal vesicles and coagulating gland, were collected, weighed, fixed in formalin and imaged. GUT weights were significantly lower in CA-treated mice compared to untreated controls in a time dependent manner (P<0.01). Morphometric image analysis performed on the GUT to measure the prostate area revealed significant shrinkage of the prostate gland in CA-treated mice vs. the corresponding controls (P<0.001). Histopathological distribution analysis of normal, prostatic intraepithelial neoplasia (PIN) and tumor glands showed a decrease in the PIN but not normal or cancer glands in 15-week-old CA-treated mice compared to controls. However, similar analysis showed a dramatic decrease of cancer gland shrinkage in 20-week-old CA-treated mice with only marginal decreases of PIN compared to untreated controls. Immunohistochemical analysis of androgen receptor (AR) expression showed a significant decrease in nuclear localization and intensity CA-treated mice (P<0.001). Proliferation analysis of tumors by PCNA immunostaining showed a 30% reduction in 20-week-old mice treated with CA compared to untreated control mice (P<0.001). The apoptotic index in tumors if mice treated with CA increased three-fold to 3.16% compared to 1.12% on the corresponding control mice (P<0.004). Our data suggests that chemopreventive treatment with CA does not prevent the incidence of prostate cancer, however, it does inhibit the growth and progression of prostate cancer. Our findings may reveal a promising prophylactic strategy for the chemopreventive treatment of prostate cancer in high-risk individuals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 956.