title: Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.
abstract: There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wargon
authors.forename: Marina
authors.initials: M
authors.lastname: Riggio
authors.forename: Sebastián
authors.initials: S
authors.lastname: Giulianelli
authors.forename: Gonzalo R
authors.initials: GR
authors.lastname: Sequeira
authors.forename: Paola
authors.initials: P
authors.lastname: Rojas
authors.forename: María
authors.initials: M
authors.lastname: May
authors.forename: María L
authors.initials: ML
authors.lastname: Polo
authors.forename: María A
authors.initials: MA
authors.lastname: Gorostiaga
authors.forename: Britta
authors.initials: B
authors.lastname: Jacobsen
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Virginia
authors.initials: V
authors.lastname: Novaro
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology*; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D011372:Progestins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011980:Receptors, Progesterone / Q000378:metabolism*
chemical_list: C530105:Ccnd1 protein, mouse; C489428:Myc protein, mouse; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D011372:Progestins; D016271:Proto-Oncogene Proteins c-myc; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D019938:Cyclin D1; D015735:Mifepristone; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3
keywords: AIB1; MYC; SMRT; antiprogestin therapy; antiprogestins; breast cancer; cyclin D1; hormone responsiveness; mifepristone; progesterone receptor isoforms