Abstract 1318: Progesterone promotes estrogen induced mammary carcinogenesis through activation of RANKL

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Ovarian hormones estrogen and progesterone play a vital role in normal development and function of breast tissue. Over exposure to ovarian hormones, especially estrogens and progesterone increase the risk of breast cancer. Epidemiological and experimental studies argue that estrogens are central to its etiology. It has been demonstrated that ovary intact ACI rats given estrogen induced high incidence of mammary cancers while ovariectomized rats given the same dose of estrogen for the same length of time did not induce mammary cancers. Recently, we demonstrated that ovariectomized ACI rats given estrogen plus progesterone had a high incidence of mammary cancer. Hence, it is essential to understand the possible role of progesterone in mammary carcinogenesis. Our goal was to determine the mechanism by which progesterone promotes estrogen induced mammary carcinogenesis in ACI rats. To achieve our goal, we designed the following experiment. Ovary intact (7 week old) and ovariectomized (at 5 weeks; treatment starting at 7 weeks) rats were used in this study. The groups (n=30) tested were as follows: 1) ovary intact control (no hormone treatment); 2) ovary intact rats given 30 mg estradiol; 3) ovary intact rats given 30 mg estradiol plus 30 mg mifepristone(progesterone antagonist); 4) ovary intact rats given 30 mg progesterone; 5) ovariectomized control (no hormone treatment); 6) ovariectomized rats given 30 mg estrogen; and 7) ovariectomized rats given 30 mg estradiol plus 30 mg progesterone. Mammary glands were surgically excised and snap frozen in liquid nitrogen and stored at -80°C from a subset (n=4) animals after four weeks of treatment. Mammary carcinogenesis was followed for nine months in rest of the animals. Estradiol induced mammary cancers in ovary intact rats and not in ovariectomized rats. Treatment with progesterone plus estradiol to ovariectomized rats induced high incidence of mammary cancer. Mifepristone treatment inhibited estradiol induced mammary carcinogenesis in ovary intact rats. Pathway focused microarray analysis of mammary glands from the rats of different groups and treatment indicated alterations in apoptosis and PI3K pathways. Estrogen plus progesterone treatment down regulated apoptotic genes such as Apaf1, Bad, Bax, Bid, Casp9 and up regulated Nfkb1, Nfkbia and Tollip when compared with estrogen alone treatment in ovariectomized rats. RANK and RANKL expression was significantly increased by estradiol plus progesterone, than estradiol alone or ovariectomized controls. We have observed that progesterone mediates estrogen induced mammary carcinogenesis through RANKL and RANK both at transcriptional and translational levels. Our results clearly demonstrate that progesterone promotes activation of NF-κB by activation of RANKL in estrogen induced carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1318. doi:10.1158/1538-7445.AM2011-1318