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.
Highlights
The process of breast oncogenesis is believed to span up to several decades
The E2 dose that was required for substantial or virtually complete suppression of invasiveness in the three estrogen receptor (ER)+ cell lines is at the low end of the literature consensus for both plasma and breast tissue levels of E2 in pre-menopausal (1.4nM–4.2nM) or post-menopausal (0.027 + 0.01 nM in plasma; 1.4nM + 0.7 in breast tisue) women [5, 6, 42, 43]
The results of this study reveal that the positive effect of progestins on invasiveness of ER+ breast cancer cells has two components: 1. rescue of invasiveness from estrogen repression at relatively low progestin concentrations that is mediated exclusively by progesterone receptor (PR) isoform A and 2. estrogen-independent induction of invasiveness at high progestin concentrations that is mediated exclusively by PR isoform B
Summary
Most (> 78 percent) of newly diagnosed breast cancer cases occur in women that are older than 50 years [1] and the median age at diagnosis is 61 years [2]. ER+ tumors are exquisitely sensitive to anti-estrogen therapy. ER+ breast cancer is often metastatic at the time of diagnosis and metastatic ER+ tumors frequently appear after many years of dormancy [3, 4]. It is necessary to understand more about deregulated molecular mechanisms that confer invasive properties on ER+ breast cancer cells. Both pre-menopausal and post-menopausal events that influence breast tumor invasiveness are clinically highly significant in breast tumor progression. Profound decreases in the levels of circulating estrogen www.impactjournals.com/oncotarget and progesterone are a hallmark of post-menopausal physiology in post-menopausal women, breast, endometrial and adipose tissues contain much higher levels of estrogen and progesterone, compared to plasma levels of the hormones [5,6,7,8,9]
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