Abstract 5038: Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone

Abstract

Abstract Introduction: High expression of the progesterone receptor (PR) isoform A, relative to PR isoform B, is clinically associated with progression to invasiveness in estrogen receptor (ER)-positive breast cancer and lower disease free survival. This is apparently at odds with in vitro studies implicating PR-B in mediating progestin-induced invasiveness. As the in vitro studies were conducted in the absence of estrogen (E2) signaling, we considered the possibility that modulation of E2 action may comprise a distinct aspect of the regulation of invasiveness by progestins. Methods: Standard ER+/PR+ and ER+/PR+/HER2+ breast cancer cell line models were studied, as well as recombinant cells expressing a single PR isoform. For the progestin hyper-sensitization studies, PR-A was over-expressed by lentiviral infection. Hormonal influence on invasiveness was studied using the Boyden chamber assay. Gene expression was examined by Illumina DNA microarray analysis and by Taq-Man real time RT-PCR assays. Results: E2 strongly suppressed invasiveness of ER+ breast cancer cells at concentrations below 0.01nM. At low (< 1 nM) concentrations, progesterone, R5020 and medroxyprogesterone acetate completely abrogated the inhibition of invasiveness by E2. It was only in a higher (5nM - 50 nM) concentration range that progestins induced invasiveness in the absence of E2. The ability of progestins to rescue invasiveness from E2 regulation was exclusively mediated by PR-A whereas PR-B mediated the E2-independent component of progestin-induced invasiveness. Overexpression of PR-A in PR-A+/PR-B+ cells lowered the progestin concentration needed to completely rescue invasiveness (to < 0.2 nM). Progesterone opposed E2 regulation of a distinctive set of genes, exclusively through PR-A. Conclusion: At relatively low concentrations, progesterone influences breast cancer cell invasiveness by rescuing it from E2 regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of E2 signaling, through PR-B. The findings establish a direct functional link between PR-A and progression of luminal breast cancer in the context of the entire range of pre- and post-menopausal plasma and breast tissue estrogen and progesterone levels. Citation Format: Thomas B. McFall, Mugdha Patki, Rayna Rosati, Manohar Ratnam. Role of the short isoform of the progesterone receptor in hormone-regulated invasiveness of breast cancer cells at pre- and post-menopausal levels of estrogen and progesterone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5038. doi:10.1158/1538-7445.AM2015-5038