Abstract 1284: Estrogen receptor alpha transcriptionally regulates p53 in MCF7 human breast cancer cells

Abstract

Abstract The p53 tumor suppressor plays a critical role in maintaining genome stability. In response to genotoxic stress, p53 induces target genes for cell cycle arrest, apoptosis, and DNA repair. While p53 is the most commonly mutated gene in all cancers, it is only mutated in 20% of breast cancers. Interestingly, 70% of all breast cancer cases are estrogen receptor (ER) positive and are associated with wild type p53 expression. An ER-positive breast cancer diagnosis generally indicates good patient prognosis and treatment responsiveness with anti-estrogens such as tamoxifen. The relationship between ERα and p53 remains poorly defined. Here, we found that ERα positively regulates p53 expression. Specifically, knockdown of ERα decreases the amount of p53 along with its downstream target p21, a regulator of cell cycle arrest, in MCF7 breast cancer cells. Furthermore, we found that ERα transcriptionally regulates p53 expression via binding to the p53 promoter. Luciferase promoter reporter experiments showed that two estrogen receptor element half sites located at nt −1828 and −1611 from the p53 transcriptional start site responded to addition of ERα with increased reporter activity. Mutation of those two sites resulted in no reporter activity. To determine the biological significance of ERα regulation of p53, we found that knockdown of ERα desensitized cells to growth arrest and cell death upon treatment with DNA damage-inducing drugs in a p53-dependent manner. Conversely, cells overexpressing ERα were sensitized to growth arrest and cell death upon DNA damage-inducing drugs via the p53 pathway. Together, these results provide an insight into the reciprocal regulation of p53 and ERα at the transcript level and how their pathways interact in ER-positive breast cancers under basal and stress conditions. 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 1284. doi:1538-7445.AM2012-1284