Ligand-Independent Activation of Androgen Receptors by Rho GTPase Signaling in Prostate Cancer

Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.