Abstract P3-05-09: Glucocorticoid receptor modulation affects ER+ breast cancer cell proliferation

Abstract

Abstract Early-stage ER+ breast cancer with high tumor glucocorticoid receptor (GR) expression is associated with improved long term relapse-free survival compared to tumors with low GR expression. In addition, activation of GR inhibits estradiol-mediated ER+ BC cell proliferation. This finding led us to hypothesize that GR and ER engage in nuclear receptor cross-talk to affect pro-proliferative gene expression, thus contributing to a better outcome in ER+/GR+ BC patients. To better understand the mechanisms by which ER/GR co-activation contributes to this more indolent phenotype, we performed ChIP-sequencing and gene expression analyses in ER+/GR+ BC cell lines (MCF-7 and T47D). We found that co-activation of ER and GR led to decreased ER+ BC cell proliferation in vitro. Furthermore, following co-activation of ER/GR, there was decreased gene expression of key cell cycle genes (e.g. CDK6, CDK2 and CCNE1) compared to ER-activation alone. Studies are underway to determine if this decrease in gene expression is associated with less CDK activity as well as a slowing of cell cycle progression. We also wanted to know if GR activation with a pure agonist versus a mixed GR modulator was required for decreasing ER-mediated cell proliferation. Based on our previous work (DC West et al. MCR 2016), we hypothesized that ligand-mediated GR activation could be working by preventing access of ER to regulatory regions of pro-proliferative genes rather than causing direct GR agonist-mediated gene expression. To examine this question, we used a GR modulator, mifepristone (expected to alter ER-mediated gene expression indirectly). Indeed we found that a GR modulator also reduced ER-mediated cell proliferation. We are currently testing the mechanisms by which GR modulators affect estradiol-mediated cell cycle gene expression. Taken together, these studies suggest that modulation of GR activity could be an effective approach to decrease ER+ tumor cell proliferation. Xenograft studies are underway to examine whether the addition of GR modulation to tamoxifen will improve tumor shrinkage compared to tamoxifen alone. Citation Format: Tonsing-Carter E, Bowie KR, West DC, Harkless RV, Hernandez KM, Conzen SD. Glucocorticoid receptor modulation affects ER+ breast cancer cell proliferation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-09.