[The role of estrogen receptor alpha in breast cancer cell proliferation mediated by progestins].
In C4-HD murine mammary carcinomas and in human breast cancer T47D cells, we showed that medroxyprogesterone acetate (MPA) induces a nuclear physical association between estrogen receptor alpha (ERa) and progesterone receptors (PR). The blockade of ERa inhibits cell proliferation mediated by progestins. We hypothesized that this nuclear association between ERa/PR is necessary to trigger progestin-induced cell proliferation and tumor growth. We demonstrated that fulvestrant (FUL, ICI182.780) induced complete regression of C4-HD tumors growing with progestins. MPA treatment induced an early increase in both CCND1 and MYC expression in T47D cells. The blockade of ERa prevented the MPA-dependent transcription of both genes. Specific binding of PR/ERa was observed at the same MPA-sensitive regions at the CCND1 and MYC gene promoters after chromatin immunoprecipitation (ChIP) analysis. ICI inhibited binding of ERa to both gene regulatory sequences while PR binding was unaffected. The nuclear colocalization between both receptors in T47D cells was confirmed by: confocal microscopy, Duolink assays and co-immunoprecipitation assays. In breast cancer samples we also observed a nuclear interaction between both steroid receptors. Our results indicate that the presence of ERa interacting with activated PR at the CCND1 and MYC promoters is required to trigger progestin-induced gene transcription and cell proliferation in breast cancer cells.
Instituto de Biología y Medicina Experimental, IByME-CONICET, Buenos Aires, 1428 Buenos Aires, Argentina.
Sebastián
S
Giulianelli
José P
JP
Vaqué
Victoria
V
Wargon
Rocío
R
Soldati
Silvia I
SI
Vanzulli
Rubén
R
Martins
Eduardo
E
Zeitlin
Luisa
L
Helguero
Caroline
C
Lamb
Alfredo A
AA
Molinolo
J Silvio
JS
Gutkind
Claudia
C
Lanari
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D016259:Genes, myc; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051189:Murinae; D011372:Progestins / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D011372:Progestins; D011980:Receptors, Progesterone; D019938:Cyclin D1; D000077267:Fulvestrant; D004958:Estradiol; D017258:Medroxyprogesterone Acetate