Estrogen receptor alpha mediates progestin-induced mammary tumor growth by interacting with progesterone receptors at the Cyclin D1/MYC promoters.

GIULIANELLI, SEBASTIÁN; VAQUE, JP; SOLDATI, ROCÍO; WARGON, VICTORIA; VANZULLI, SILVIA; MARTINS, RUBÉN; ZEITLIN, E.; MOLINOLO, ALFREDO; HELGUERO, LUISA; LAMB, CAROLINE A.; GUTKIND, J. SILVIO; LANARI, CLAUDIA

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2012 vol. 72

0008-5472

Synthetic progesterone used in contraception drugs (progestins) can promote breast cancer growth but the mechanisms involved are unknown. Moreover, it remains unclear whether cytoplasmic interactions between the progesterone receptor (PR) and estrogen receptor alpha (ER) is required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ER in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ER, as well as rapid nuclear co-localization of activated ER with PR. Treatment with the pure anti-estrogen fulvestrant to block ER disrupted the interaction of ER and PR in vitroin vitro and induced the regression of MPA-dependent tumor growth in vivo. ER blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. in vivo. ER blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ER and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation. CCND1 and MYC promoters. Interestingly, blockade or RNAimediated silencing of ER inhibited ER, but not PR binding to both regulatory sequences, indicating that an interaction between ER and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ER-PR association on target gene promoters is essential for progestin-induced cell proliferation.