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
Victoria Wargon
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
V.W. and M.R. contributed equally to this work
Search for more papers by this authorMarina Riggio
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
V.W. and M.R. contributed equally to this work
Search for more papers by this authorSebastián Giulianelli
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorGonzalo R. Sequeira
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorPaola Rojas
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría May
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría L. Polo
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría A. Gorostiaga
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorBritta Jacobsen
University of Colorado Anschutz Medical Campus, Aurora, CO
Search for more papers by this authorAlfredo Molinolo
Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD
Search for more papers by this authorVirginia Novaro
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorCorresponding Author
Claudia Lanari
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Correspondence to: Claudia Lanari, IBYME-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina, Tel.: +054-011-4783-2869, Fax: +054-011-4786-2564, E-mail: [email protected]Search for more papers by this authorVictoria Wargon
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
V.W. and M.R. contributed equally to this work
Search for more papers by this authorMarina Riggio
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
V.W. and M.R. contributed equally to this work
Search for more papers by this authorSebastián Giulianelli
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorGonzalo R. Sequeira
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorPaola Rojas
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría May
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría L. Polo
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorMaría A. Gorostiaga
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorBritta Jacobsen
University of Colorado Anschutz Medical Campus, Aurora, CO
Search for more papers by this authorAlfredo Molinolo
Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD
Search for more papers by this authorVirginia Novaro
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Search for more papers by this authorCorresponding Author
Claudia Lanari
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Correspondence to: Claudia Lanari, IBYME-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina, Tel.: +054-011-4783-2869, Fax: +054-011-4786-2564, E-mail: [email protected]Search for more papers by this authorAbstract
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.
Abstract
What's new?
There is emerging interest in understanding the role of progesterone receptors (PRs)—of which two isoforms have been described, PRA and PRB—in breast cancer. This study investigates the proliferative effect of antiprogestins depending on the relative expression of PRA and PRB. The results provide mechanistic evidence that the responsiveness of breast cancer to antiprogestin treatment is determined by the ratio of expression of PRA and PRB isoforms. Antiprogestins selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters. The results may pave the way for a personalized use of antiprogestins in breast cancer treatment.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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