Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells.
Overexpression of androgen receptor (AR) decreases estrogen receptor alpha (ERalpha) transactivation, which plays a basic role in hormone-dependent breast cancer. This transcriptional interference can be due to shared coactivators. Here we demonstrated that in MCF-7 cells ARA70, an AR-specific coactivator, interacted with endogenous ERalpha, increasing its transcriptional activity, and it was recruited to the pS2 gene promoter. Moreover, a dominant negative ARA70 down-regulated ERalpha transcriptional activity as well as pS2 mRNA. ARA70 overexpression reversed the AR down-regulatory effect on ERalpha signaling. However, in the presence of a progressive increase of transfected AR, ARA70 switched into enhancing the inhibitory effect of AR on ERalpha signaling. These opposite effects of ARA70 were further evidenced by coimmunoprecipitation assay in MCF-7wt, MCF-7-overexpressing AR, and HeLa cells, exogenously expressing an excess of ERalpha with respect to AR or an excess of AR with respect to ERalpha. Thus, ARA70 is a coactivator for ERalpha and may represent a functional link between ERalpha/AR modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells.
Lanzino
Marilena
M
Department of Pharmacobiology, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
De Amicis
Francesca
F
McPhaul
Michael J
MJ
Marsico
Stefania
S
Panno
Maria Luisa
ML
Andò
Sebastiano
S
D015153:Blotting, Western; D001943:Breast Neoplasms; D004247:DNA / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007163:Immunosorbent Techniques; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; D013196:Dihydrotestosterone; D004247:DNA