Artículo
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
Wargon, Victoria
; Riggio, Marina
; Giulianelli, Sebastian Jesus
; Sequeira, Gonzalo Ricardo
; Rojas, Paola Alejandra
; May, Maria
; Polo, Maria Laura
; Gorostiaga, Maria Alicia
; Jacobsen, Britta; Molinolo, Alfredo; Novaro, Virginia
; Lanari, Claudia Lee Malvina
Fecha de publicación:
12/11/2014
Editorial:
John Wiley & Sons Inc
Revista:
International Journal Of Cancer. Journal International Du Cancer.
ISSN:
0020-7136
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(CCT-CENPAT)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - CENPAT
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - CENPAT
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Wargon, Victoria; Riggio, Marina; Giulianelli, Sebastian Jesus; Sequeira, Gonzalo Ricardo; Rojas, Paola Alejandra; et al.; 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; John Wiley & Sons Inc; International Journal Of Cancer. Journal International Du Cancer.; 136; 11; 12-11-2014; 2680-2692
Compartir
Altmétricas