A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase

Prostate cancer progresses from a hormone-sensitive, androgen-dependent sta ge to a hormone-refractory, androgen-independent tumor. The androgen recept or pathway functions in these androgen-independent tumors despite anti-andr ogen therapy. In our LAPC-4 prostate cancer model, androgen-independent sub lines expressed higher levels of the HER-2/neu receptor tyrosine kinase tha n their androgen-dependent counterparts. Forced overexpression of HER-2/neu in androgen-dependent prostate cancer cells allowed ligand-independent gro wth. HER-2/neu activated the androgen receptor pathway in the absence of li gand and synergized with low levels of androgen to 'superactivate' the path way. By modulating the response to low doses of androgen, a tyrosine kinase receptor can restore androgen receptor function to prostate cancer cells, a finding directly related to the clinical progression of prostate cancer.