Caveolin-1 potentiates estrogen receptor α (ERα) signaling -: Caveolin-1 drives ligand-independent nuclear translocation and activation of ERα

Estrogen receptor alpha (ER alpha) is a soluble protein that mediates the effects of the gonadal estrogens such as 17 beta-estradiol. Upon ligand binding, a cytoplasmic pool of ER alpha translocates to the nucleus, where it acts as a transcription factor, driving the expression of genes that contain estrogen-response elements. The activity of ERa is regulated by a number of proteins, including cytosolic chaperones and nuclear cofactors, Here, we show that caveolin-1 potentiates ER alpha-mediated signal transduction, Coexpression of caveolin-1 and ER alpha resulted in ligand-independent translocation of ER alpha to the nucleus as shown by both cell fractionation and immunofluorescence microscopic studies. Similarly, caveolin-1 augmented both ligand-independent and ligand-dependent ER alpha signaling as measured using a estrogen-response element-based luciferase reporter assay, Caveolin-1-mediated activation of ER alpha was sensitive to a well known ER antagonist, 4-hydroxytamoxifen. However, much higher concentrations of tamoxifen were required to mediate inhibition in the presence of caveolin-1. Interestingly, caveolin-1 expression also synergized with a constitutively active, ligand-independent ER alpha mutant, dramatically illustrating the potent stimulatory effect of caveolin-1 in this receptor system. Taken together, our results identify caveolin-1 as a new positive regulator of ER alpha signal transduction.