Abstract 2566: Positive cross-regulatory loop links ZBTB7A to estrogen receptor alpha expression in breast cancer

Abstract

Abstract In breast development and tumorigenesis the biological functions of estrogen are mediated by estrogen receptor alpha (ERα). Approximately 70% of breast cancers are classified as ERα positive and are therefore candidates to receive various forms of endocrine therapy. De novo or acquired resistance to endocrine therapies limits their clinical effectiveness. Identification of novel targets is critical to combat disease progression. Our lab has recently discovered that ZBTB7A suppresses glycolysis by transcriptionally repressing key genes within the glycolytic pathway in various cancer types (Liu, X.S., et al. 2014). Currently, ZBTB7A is proposed to be an oncogene in breast cancer (Zu, X., et al. 2011), however its function in ERα positive breast cancers has yet to be fully addressed. Using publically available datasets, we found that in luminal breast cancers relapse free survival was improved for patients whose tumors expressed high levels of ZBTB7A. Gene expression analysis of TCGA datasets revealed that ZBTB7A and ERα are highly correlated in human breast tumors prompting us to evaluate their potential cross regulation. ERα mRNA and protein levels were significantly decreased upon ZBTB7A silencing both in MCF-7 and T47D breast cancer cell lines. Upon estradiol stimulation, ZBTB7A silencing reduced ERα target gene expression and estrogen response element driven luciferase reporter activity. Additionally, silencing of ZBTB7A inhibited estradiol-induced proliferation and decreased sensitivity to tamoxifen in MCF-7 and T47D cells. These data suggest that ZBTB7A may be required to mediate the pro-proliferative signal of estradiol through its regulation of ERα expression in breast cancer cell lines. To evaluate the potential regulation of ERα on ZBTB7A, ERα was silenced and ZBTB7A mRNA and protein expression were determined. ERα silencing had no effect on ZBTB7A mRNA levels, but led to decreased ZBTB7A protein expression. These effects on ZBTB7A protein expression were attenuated by the presence of the proteasomal inhibitor MG132. Together, these data suggest a model in which ZBTB7A promotes ERα expression at the transcript level while ERα stabilizes ZBTB7A post-transcriptionally conferring a positive feedback loop and sensitivity to estradiol and endocrine therapies. ZBTB7A may contribute to the transcriptional program maintaining a hormone and endocrine therapy responsive phenotype in breast cancer. Citation Format: Mary Ellen Molloy, Monika Lewinska, ThanhThao Nguyen, Zhi-Min Yuan. Positive cross-regulatory loop links ZBTB7A to estrogen receptor alpha expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2566. doi:10.1158/1538-7445.AM2017-2566