Abstract P1-08-02: Short-Term Pregnancy Levels of Estradiol Delays Mammary Tumor Development by Altering PI3K/AKT Pathway in Her2/neu Mice

Abstract

Abstract Approximately 20-30% of all breast cancers overexpress the human epithelial growth factor receptor 2 (Her2). Breast cancers that overexpress Her2 have been associated with a more aggressive phenotype and decreased survival. Currently, the FDA has only approved trastuzumab, a recombinant monoclonal antibody against the Her2 receptor, for treatment of Her2- overexpressing breast cancer. Even though trastuzumab has been effective, many breast cancers do not respond to treatment or they eventually progress to a resistant state. Hence, several research investigations are underway to identify therapies besides trastuzumab that could be used for the treatment of Her2-positive breast cancer. It has been earlier demonstrated that uniparous Her2/neu transgenic mice developed smaller mammary tumors and these tumors had significantly decreased metastatic potential. Also, we had earlier demonstrated that short-term treatment with pregnancy levels of estradiol was very effective in delaying tumor progression and decreasing tumor burden. In this present investigation, we have attempted to understand the molecular mechanisms underlying this anti-tumor effect of short-term pregnancy levels of estradiol treatment against Her2/neu driven mammary carcinogenesis. Seven week old activated Her2/neu (murine-mammary-tumor virus (MMTV)-c-neu) FVB transgenic mice were treated for 3 weeks with 100mg of estradiol in silastic capsules. We have shown that this dose of estradiol treatment mimics pregnancy levels of the hormone in circulation. Control animals received empty silastic capsules for the same duration. Mice were palpated once every week for nine months to monitor the development of mammary cancer. Histopathological examination was performed to confirm the carcinomatous nature of the palpable tumors. A group (n=3) of mice were terminated from control and estradiol treated groups immediately after three weeks of treatment, and also, at 6 and 12 weeks post withdrawal of the treatment. Mammary tumor and normal mammary tissue were excised, snap-frozen in liquid nitrogen and stored at −80°C. Protein and total RNA were extracted from these tissues. Pathway focused microarray analysis was done on the PI3K/AKT pathway. Results demonstrate that, in parous and estrogen treated mice, proteins and genes involved in tumor-suppression (Mtcp1,Rbl2,Srf and Ywhah) and immune response (Cd14,Tlr4) were upregulated; which have been shown to play a role in reducing tumors by induction of apoptosis. This trend in gene expression alteration is present in both normal and mammary tumor tissue in the estradiol treated and parous groups and demonstrates that short-term pregnancy levels estrogen is altering the PI3K/AKT pathway; which correlates with our previous findings that short-term estradiol treatment is effective in tumor delay. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-08-02.