title: 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.
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.
authors.affiliation: Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: McFall
authors.affiliation: Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Patki
authors.affiliation: Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Rayna
authors.initials: R
authors.lastname: Rosati
authors.affiliation: Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Manohar
authors.initials: M
authors.lastname: Ratnam
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D017698:Postmenopause / Q000378:metabolism; D017697:Premenopause / Q000378:metabolism; D011397:Promegestone / Q000494:pharmacology; D020033:Protein Isoforms; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D020033:Protein Isoforms; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D004958:Estradiol; D011397:Promegestone
keywords: breast cancer; estrogen receptor; invasiveness; progesterone receptor