Mechanisms of arsenic-induced acquired androgen independence. Abbreviations: AR, androgen receptor; ARE, androgen responsive element; As, arsenic; GF, growth factors; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPK kinase kinase; PSA, prostate-specific antigen. It is known that exposure to arsenic initiates GF receptor signaling and Ras-dependent activation of MEK1/2 and ERK1/2. (A) As prostate cancer progresses to androgen independence, the growth factors production increases. Growth factor signal transduction pathways have been shown to stimulate AR activation. All these growth factors use the Ras/MAPK pathway for a portion of their signal transduction. Binding of GF results in dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The GF receptor activates ras which in turn activates Raf, which phosphorylates and activates MEK, which in turn, phophorylates and activates ERK. Activated MAPK can regulate targets in the cytosol and also translocate to the nucleus causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1, which contribute to proliferation. (B) HER-2/neu promotes phosphorylation of AR at multiple sites even in the presence of very low androgen levels. HER-2/neu indirectly activates MAPK. MAPK might phosphorylate the AR, creating an androgen-independent receptor.