Role of the short isoform of the progesterone receptor in breast cancer cell invasiveness at estrogen and progesterone levels in the pre- and post-menopausal ranges
Year: 2015
Type: article
Abstract: // Thomas McFall 1 , Mugdha Patki 1 , Rayna Rosati 1 , Manohar Ratnam 1 1 Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, MI, USA Correspondence to: Manohar Ratnam, e-mail: [email protected] Thomas McFall, e-mail: [email protected] Mugdha Patki, e-mail: [email protected] Rayna Rosati, e-mail: [email protected] Keywords: breast cancer, progesterone receptor, estrogen receptor, invasiveness Received: June 09, 2015 Accepted: August 14, 2015 Published: August 24, 2015 ABSTRACT Overexpression of the progesterone receptor (PR) isoform A (PR-A) is a negative prognosticator for estrogen receptor (ER)-positive breast cancer but in vitro studies have implicated PR-B in progestin-induced invasiveness. As estrogen is known to suppress invasiveness and tumor progression and as the in vitro studies were conducted in models that either lacked ER or excluded estrogen, we examined the role of PR isoforms in the context of estrogen signaling. Estrogen (< 0.01nM) strongly suppressed invasiveness in various ER+ model cell lines. At low (< 1nM) concentrations, progestins completely abrogated inhibition of invasiveness by estrogen. It was only in a higher (5 nM — 50 nM) concentration range that progestins induced invasiveness in the absence of estrogen. The ability of low dose progestins to rescue invasiveness from estrogen regulation was exclusively mediated by PR-A, whereas PR-B mediated the estrogen-independent component of progestin-induced invasiveness. Overexpression of PR-A lowered the progestin concentration needed to completely rescue invasiveness. Among estrogen-regulated genes, progestin/PR-A counter-regulated a distinctive subset, including breast tumor progression genes (e.g., HES1, PRKCH, ELF5, TM4SF1), leading to invasiveness. In this manner, at relatively low hormone concentrations (corresponding to follicular stage and post-menopausal breast tissue or plasma levels), progesterone influences breast cancer cell invasiveness by rescuing it from estrogen regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of estrogen signaling, through PR-B. The findings point to 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 hormone levels.
Source: Oncotarget
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W2190463667