Endogenous coactivator ARA70 interacts with estrogen receptor α (ERα) and modulates the functional ERα/androgen receptor interplay in MCF-7 cells

Overexpression of androgen receptor (AR) decreases estrogen receptor alpha (ER alpha) 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 ER alpha, increasing its transcriptional activity, and it was recruited to the pS2 gene promoter. Moreover, a dominant negative ARA70 down-regulated ER alpha transcriptional activity as well as pS2 mRNA. ARA70 overexpression reversed the AR down-regulatory effect on ER alpha signaling. However, in the presence of a progressive increase of transfected AR, ARA70 switched into enhancing the inhibitory effect of AR on ER alpha 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 ER alpha with respect to AR or an excess of AR with respect to ER alpha. Thus, ARA70 is a coactivator for ER alpha and may represent a functional link between ER alpha/AR modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells.