Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratioviaAIB1 or SMRT recruitment to theCCND1andMYCpromoters
| Autor: | Victoria Wargon, Claudia Lanari, Sebastián Giulianelli, Britta M. Jacobsen, Gonzalo Ricardo Sequeira, Maria May, Maria Alicia Gorostiaga, Alfredo A. Molinolo, Maria Laura Polo, Paola Alejandra Rojas, Marina Riggio, Virginia Novaro |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
medicine.medical_specialty Cell growth Chemistry Context (language use) Endocrinology Cyclin D1 Oncology Internal medicine Nuclear receptor coactivator 3 Coactivator medicine Cancer research Histone deacetylase neoplasms Chromatin immunoprecipitation Corepressor hormones hormone substitutes and hormone antagonists |
| Zdroj: | International Journal of Cancer. 136:2680-2692 |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.29304 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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