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

GIULIANELLI, SEBASTIAN; VAQUE, JOSE PEDRO; SOLDATI, ROCIO; WARGON, VICTORIA; VANZULLI, SILVIA; MARTINS, RUBEN; ZEITLIN, EDUARDO; MOLINOLO, ALFREDO; HELGUERO, LUISA; LAMB, CAROLINE; GUTKIND, J. SILVIO; LANARI, CLAUDIA

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2012 p. 2416 - 2427

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 (ERa) is required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ERa in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ERa, as well as rapid nuclear co-localization of activated ERa with PR. Treatment with the pure anti-estrogen fulvestrant to block ERa disrupted the interaction of ERa and PR and induced the regression of MPA-dependent tumor growth in vivo. ERa blockade also prevented an MPA-induced increase in CYCLIN D1 and MYC expression. Chromatin immunoprecipitation studies demonstrated that MPA triggered binding of ERa and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ERa inhibited ERa, but not PR binding to both regulatory sequences, indicating that an interaction between ERa and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear co-localization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ERa-PR association on target gene promoters is essential for progestin-induced cell proliferation.