Abstract P1-08-01: Short-Term Exposure to Pregnancy Levels of Estrogen Alters Key Molecular Pathways Involved in Breast Cancer Development

Abstract

Abstract Breast cancer is the most common cancer in women worldwide and attempts at prevention of breast cancer are important areas of clinical and experimental investigations. Interestingly, a full-term pregnancy before the age of twenty is the only natural phenomenon known that can drastically reduce the risk of breast cancer in women. The universal protective effect of early pregnancy is clearly a major consideration in devising breast cancer prevention strategies. Rats that have been exposed to carcinogens before or after undergoing a full-term pregnancy are protected from mammary carcinogenesis. Hormonal prevention strategies have used exogenous hormonal treatment to mimic the protective effect of early full-term pregnancy against breast cancer. We have demonstrated that short-term treatment with pregnancy levels of estradiol with or without progesterone is highly effective in conferring protection against mammary carcinogenesis in rats. In order to understand the molecular mechanism of the protective effect of short-term pregnancy levels of estradiol treatment we have performed pathway focused microarrays. Nine week old female Lewis rats were divided into three groups, each consisting of 15 rats and receiving one of the following treatments: (i) control, (ii)10 microgram estradiol (non-protective dose), and (iii) 200 microgram estradiol (protective dose). Each treatment was given in the form of silastic capsule and continued for the length of gestation (3 weeks) in rats. At the end of the treatment, the silastic capsule was removed. The rats were then terminated, 8 and 16 weeks after removal of the hormone treatment. Mammary glands were removed, immediately snap frozen in liquid nitrogen and stored at −80°C. Total RNA and protein were extracted and used for gene and protein expression analyses. Our data indicate that several proteins and genes which are involved in apoptosis, DNA repair and growth inhibition (Bax, Bclaf1, Cidea, Fas, Tnfsf10) are upregulated in the mammary glands of rats that received pregnancy levels of estradiol treatment compared to the rats that received non-pregnancy levels of estradiol treatment and untreated controls. By contrast, there were consistent decreasing levels of proteins and genes involved in growth regulation, angiogenesis, anti-apoptosis and cell cycle regulation (Dad1 Faim, Naip2, Xiap) in the mammary glands of pregnancy level estradiol treated rats when compared to the non pregnancy level estradiol treated rats and untreated controls. These alterations were similar at both the time points after withdrawal of treatments indicating that these changes are constitutive. In conclusion, short-term treatment with pregnancy levels of estradiol resulted in persistent down-regulation of growth promotion, cell cycle, anti-apoptosis, angiogenesis and oncogenesis. On the other hand, the same protective treatment persistently enhanced growth inhibition, apoptosis and DNA repair. The data obtained could be helpful to understand the mechanisms involved in short-term pregnancy level estradiol-induced protection and will also facilitate the identification of biomarkers associated with protection. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-08-01.