Abstract P5-03-06: Progesterone Activates MAPK Pathway in Estrogen Induced Mammary Carcinogenesis

Abstract

Abstract In women, breast cancer is the most prevailing endocrine-related malignancy. Epidemiological and experimental studies argue that estrogens are central to its etiology. Estrogen-induced carcinogenesis in ACI rats is highly relevant as a model for human breast cancer. These estrogen-induced cancers exhibit aneuploidy, as do invasive ductal mammary carcinomas in women. 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. In this context, it is essential to understand the possible role of progesterone, if any, as the other main ovarian hormone in mammary carcinogenesis. Our goal was to determine the role of progesterone in mammary cancer development by using carcinogenesis induced solely by hormones in ACI rats. To achieve our goal, we designed the following experiment. Ovary intact and ovariectomized 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; 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) of intact animals after four weeks of treatment and ovariectomized rats after twelve weeks of treatment. In rest of the animals mammary carcinogenesis was followed for nine months. As expected, estradiol induced mammary cancers in ovary intact rats and not in ovariectomized rats. Addition of progesterone to ovariectomized rats treated with estradiol induced high incidence of mammary cancer. Mifepristone treatment inhibited mammary carcinogenesis in ovary intact rats receiving estradiol. Pathway focused microarray analysis of mammary glands from the rats of different groups and treatment indicated alterations in apoptosis, MAPK and PI3K pathways. Estrogen plus progesterone treatment down regulated apoptotic genes such as Apaf1, Bad, Bax, Bid, Casp9 and up regulated Mapk3, Grb10, Itgb1, PrKca, Prkcz and Map4k1, Map2k1ip1, Mapk8ip2, Mapkapk5 in PI3K and MAPK pathways respectively when compared with estrogen alone treatment. We have observed differences both at transcriptional and translational levels. Our results clearly demonstrate the significance of progesterone in mammary carcinogenesis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-06.