Abstract 5567: Short-term pregnancy levels of estradiol delays Her-2 positive mammary tumor development by altering key signaling pathways

Approximately 20-30% of all breast cancers overexpress the human epidermal growth factor receptor 2 (Her2). Breast cancers that overexpress Her2 have been associated with a more aggressive phenotype and decreased disease free survival. It has been demonstrated that uniparous Her2/neu transgenic mice developed smaller mammary tumors and these tumors had significantly decreased metastatic potential despite that this cancer type is phenotypically ER negative. 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 activated Her2/neu transgenic mice. 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 transgenic mice were treated for 3 weeks with 100micrograms 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 at 6 and 12 weeks post withdrawal of the treatment. Mammary tumors 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 and P53 pathway. Results from the PI3K/AKT pathway demonstrate that, in estrogen treated mice, proteins and genes involved in tumor-suppression (Mtcp1,Rbl2,Srf and Ywhah) and immune response (Cd14,Tlr4) (which have been shown to play a role in reducing tumors by induction of apoptosis) were up-regulated. Many genes involved in promoting tumorigenesis were significantly down-regulated (Birc5,Ccnb2,Mdm2) while genes involved in cell cycle regulation and apoptosis were upregulated (Dapk1, Cul9, Sesn2).This trend in gene expression demonstrates that short-term pregnancy levels estrogen is altering key pathways leading to the delay and inhibition of Her-2 positive mammary cancer. 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 5567. doi:10.1158/1538-7445.AM2011-5567