Abstract LB-74: The estrogen receptor regulates the transcription of p53 target genes in breast cancer cells

Abstract

Abstract Breast Cancer is a disease that affects thousands of women every year. A large subset of breast cancer is attributed to estrogen receptor (ER) dysregulation. Previously, our lab and others have determined the estradiol-stimulated ER cistrome in the MCF7 mammary epithelial cell line. To determine the relationship between ER and the apoptotic response, we compared our ER cistrome to a published p53 dataset. The p53 transcription factor is a tumor suppressor protein that is responsible for cell-cycle control and apoptosis. Our lab generated a doxorubicin-stimulated p53 cistrome in MCF7 cells, and we employed an integrative analysis approach examining the p53 and ER cistromes and gene expression microarray data to determine the genes coordinately regulated by both transcription factors. We identified a number of genes that are involved in the cell cycle, apoptosis, and DNA damage repair. By treating MCF7 cells with both stimuli, we found that the ER could inhibit the expression of a p53 target gene subset, thus diminishing the efficacy of the p53 program. These genes correlate with poor breast cancer clinical outcome. Moreover, we found that treatment of breast cancer cells with a combination of the anti-estrogen fulvestrant with p53 stimuli (i.e., doxorubicin and nutlin-3) leads to the synergistic enhancement of pro-apoptotic genes. Together, these data point to a set of genes essential for breast cell survival in ER-mediated breast cancer and suggest an improved paradigm for ER-positive breast cancer treatment i.e., the addition of fulvestrant with a p53 stabilizing drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-74. doi:1538-7445.AM2012-LB-74