Androgen Receptor Levels

Initial studies using both androgen-unrespon-sive Dunning rat adenocarcinoma and human prostate cancer cell lines suggested that loss of AR mRNA and protein could be a mechanism to explain the failure of androgen-ablation therapies.129,130 Subsequent immunohistochemical studies of clinical prostate cancer demonstrated that the AR is expressed in essentially all metastatic tumors, including those that continue to grow following androgen ablation.131-137 Other studies have shown that the AR in recurrent, hormone-refractory prostate cancer is expressed at levels similar to those in androgen-dependent prostate tumors.138 Recent studies using the recurrent CWR22 xenograft model and its derived cell line, CWR-R1, as well as the LNCaP C4-2 cell line derived from LNCaP cells after prolonged periods of culture in the absence of androgen suggest that the AR is expressed at similar levels in both an-drogen-dependent and recurrent tumors but is more stable in recurrent tumors in the absence of androgen.139 In addition, the concentration of androgen required for stimulation of the CWR-R1 and LNCaP C4-2 cell lines is fourfold lower than that required for androgen-de-pendent LNCaP cells. This concentration of DHT is comparable to the levels in prostates of men treated with androgen ablation. The observations that AR is expressed at relatively high levels in recurrent CWR22 human tumor xenografts and cell lines and is hypersensitive to low levels of androgens suggest that androgen signaling and the associated activation of androgen-regulated genes in human prostate tumors is sufficient to maintain tumor growth following androgen ablation. Kim et al.140 reported marked reduction in AR expression in CWR22 tumors 2 days post-castration but subsequent reexpression of AR and androgen-regulated genes in recurrent tumors 150 days postcastration to levels comparable to those observed in tumors from intact mice. Reactivation of AR expression was associated with renewed proliferation of tumor cells at 120-150

days postcastration, suggesting that this is a critical factor contributing to renewed tumor growth.

Amplification of the AR gene, which also has the potential to contribute to increased AR protein levels, has been reported in 22% of prostate cancer metastases141 and in 23%-28% of primary tumors following androgen depriva-tion.106,142 An average twofold increase in the levels of both AR and PSA proteins has been reported in prostate tumor samples with AR gene amplification compared to samples where no AR amplification was found.7,143 Increased AR protein levels in metastatic prostate tumors may also augment the sensitivity of the androgen-signal-ing axis, thereby contributing to disease progression during the course of androgen ablation. In addition, AR gene amplification and overexpression of the receptor have been reported in hormone-refractory prostate cancer following monotherapy but not in primary prostate tu-mors,7 suggesting that hormonal therapy could select for cells with an ability to maintain growth during treatment.

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