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Resolving the Coffey Paradox: what does the androgen receptor do in normal vs. malignant prostate epithelial cells?

John T Isaacs
American Journal of Clinical and Experimental Urology 2018, 6 (2): 55-61
29666833
Donald Straley Coffey completed his 85 year life's journey on November 9, 2017. In his wake, he left a legion of inspired and loyal students, fellows, and faculty colleagues from all over the world to carry on his passion both for life in general and his 50 year quest to conquer cancer. Early in his career, Dr. Coffey developed a series of animal models to study how androgen regulates the growth of both normal and abnormal prostatic epithelium. As part of these early studies, Dr. Coffey uncovered a paradox in that anti-androgen treatment given at the "wrong" time paradoxically enhanced, not inhibited, normal prostate growth. Advances over the last several years concerning the paracrine-dependent stem cell organization of the prostate provide a mechanistic explanation for this "Coffey Paradox". This is based upon the realization that the normal function of the Androgen Receptor (AR) in the paracrine-dependent stem cell organization of the prostate is to induce terminal differentiation of normal prostate epithelial cells while suppressing their growth, despite the presence of high levels of stromal cell-derived paracrine growth factors. Such growth suppression involves ligand-dependent AR binding to the Tcf-4/β-catenin 3'c-Myc enhancer in prostate epithelial cells, which inhibits c-Myc transcription needed for proliferation. Therefore, if anti-androgen is given at the wrong time, it prevents such AR-dependent c-Myc down regulation, and thus paradoxically enhances epithelial regrowth (i.e. the Coffey Paradox) induced by exogenous androgen replacement in the castration regressed prostate. In contrast to the normal prostate epithelium, in prostate cancer cells retaining AR expression, androgen-induced AR signaling no longer reduces c-Myc transcription but instead up-regulates c-Myc translation and protein stability to stimulate malignant growth. Thus, in these AR expressing prostate cancer cells, AR signaling is converted from a growth suppressor to an oncogene, which involves a gain of function to upregulate c-Myc protein expression. Such a gain of function "addicts" these prostate cancer cells to AR signaling for their proliferation and survival, which provides the rationale for therapy targeted at inhibiting such AR signaling. While therapies targeted at maximally decreasing the level of androgen ligand are the most commonly used, recent studies have documented that a subset of patients progressing on such androgen ablation (i.e. castration-resistant disease) due to their adaptive increase in AR protein expression respond positively to rapid cycling between pharmacologically high and castration low levels of circulating androgen. [i.e. Bipolar Androgen Therapy (BAT)].

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