title: Estrogen receptor alpha mediates progestin-induced mammary tumor growth by interacting with progesterone receptors at the cyclin D1/MYC promoters.
abstract: 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 (ERα) are required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ERα in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ERα, as well as rapid nuclear colocalization of activated ERα with PR. Treatment with the pure antiestrogen fulvestrant to block ERα disrupted the interaction of ERα and PR in vitro and induced the regression of MPA-dependent tumor growth in vivo. ERα blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies showed that MPA triggered binding of ERα and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ERα inhibited ERα, but not PR binding to both regulatory sequences, indicating that an interaction between ERα 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 ERα-PR association on target gene promoters is essential for progestin-induced cell proliferation.
authors.affiliation: Institute of Experimental Biology and Medicine, IBYME-CONICET, Buenos Aires, Argentina.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Giulianelli
authors.forename: José P
authors.initials: JP
authors.lastname: Vaqué
authors.forename: Rocío
authors.initials: R
authors.lastname: Soldati
authors.forename: Victoria
authors.initials: V
authors.lastname: Wargon
authors.forename: Silvia I
authors.initials: SI
authors.lastname: Vanzulli
authors.forename: Rubén
authors.initials: R
authors.lastname: Martins
authors.forename: Eduardo
authors.initials: E
authors.lastname: Zeitlin
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Luisa A
authors.initials: LA
authors.lastname: Helguero
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lamb
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D016259:Genes, myc; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D019938:Cyclin D1; D000077267:Fulvestrant; D004958:Estradiol; D017258:Medroxyprogesterone Acetate