Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

Departments of Pathology, Urology, Radiation Oncology and Wilmot Cancer Center, George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY, USA.
Oncogene (Impact Factor: 8.46). 06/2010; 29(25):3593-604. DOI: 10.1038/onc.2010.121
Source: PubMed


Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells.

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    • "These results substantiate in vitro studies showing that enforced expression of AR in AR-negative PCa cells decreases the metastatic/invasive potential of the cells [26, 29–35]. In a recent paper evaluating the role of androgen signalling in epithelial-mesenchimal transition, Zhu and Kyprianou [36] demonstrated that overexpression of AR in PCa cell lines suppresses androgen-induced epithelial-mesenchimal transition, suggesting that downregulation of AR occurring in androgen-deprived condition [37] may facilitate mesenchimal transition and promote metastasis [36]. "
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    • "In addition, AR was identified as a novel therapeutic target in UUTUCs to increase the efficacy of chemotherapeutic agents. Therapies targeting the androgen-receptor signaling axis have been used for the treatment of prostate cancer with various strategies (42,43) and may be suitable for application in the treatment of UUTUCs. Thus, the combination of AR targeted therapy with chemotherapy may increase the efficacy of therapy to cure invasive and metastatic forms of cancer previously considered to be difficult to treat. "
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    • "Our data suggest that long-term androgen-depletion may induce downregulation of AR and PSMA which may lead to a diagnostically and therapeutically elusive androgen-independent disease-state. These new data provide additional knowledge of androgen-independent prostate cancer progression compared to previous studies, which primarily focused on changes in AR ligand binding specificity that may result from gene structure changes (e.g., mutation, amplification, or spliced variant expression) or AR ligand-independent activation arising from alternative signal pathways that activate AR activity at the castration level of androgen (2,24). With respect to PSMA, it is thought that increased expression is correlated with prostate cancer progression, especially in recurrent, metastatic cancers after androgen deprivation therapy (25,26). "
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