Androgen receptor stabilization in recurrent prostate cancer is associatedwith hypersensitivity to low androgen

The androgen receptor (AR) is highly expressed in androgen-dependent and re current prostate cancer (CaP) suggesting it has a role in the growth and pr ogression of CaP. Previously proposed mechanisms for AR reactivation in rec urrent CaP include altered growth factor signaling leading to protein phosp horylation and AR mutations that broaden ligand specificity. To further est ablish a role for AR in recurrent CaP, we compared several properties of AR in relation to the growth response to low levels of androgens in model sys tems of androgen-dependent and recurrent CaP. AR from ah of the tumors and cell lines bound [H-3]R1881 with similar high affinity (mean K-d, 0.12 nM). In the absence of androgen, AR in androgen-dependent LNCaP cells was unsta ble with a degradation halftime (t(1/2)) of 3 h at 37 degreesC. In contrast , AR was 2-4 times more stable in recurrent CWR22 tumors (t(1/2), > 12 h) a nd CWR-RI or LNCaP-C4-2 cell lines (t(1/2), 6-7 h) derived from recurrent p rostate tumors. In the recurrent CWR22 tumor and its CWR-R1 cell line grown in the absence of androgen, AR immunostaining was entirely nuclear, wherea s under the same conditions BR in LNCaP-C4-2 and LNCaP cells was predominan tly nuclear but was also detected in the cytoplasm, High level expression, increased stability, and nuclear localization of AR in recurrent tumor cell s were associated with an increased sensitivity to the growth-promoting eff ects of dihydrotestosterone in the femtomolar range. The concentration of d ihydrotestosterone required for growth stimulation in CWR-R1 and LNCaP-C4-2 cells was four orders of magnitude tower than that required for androgen-d ependent LNCaP cells. The results suggest that AR is transcriptionally acti ve in recurrent CaP and can increase cell proliferation at the low circulat ing levels of androgen reported in castrated men.