Abstract
The normal development and maintenance of the prostate is dependent on androgen acting through the androgen receptor (AR). AR remains important in the development and progression of prostate cancer. AR expression is maintained throughout prostate cancer progression, and the majority of androgen-independent or hormone refractory prostate cancers express AR. Mutation of AR, especially mutations that result in a relaxation of AR ligand specificity, may contribute to the progression of prostate cancer and the failure of endocrine therapy by allowing AR transcriptional activation in response to antiandrogens or other endogenous hormones. Similarly, alterations in the relative expression of AR coregulators have been found to occur with prostate cancer progression and may contribute to differences in AR ligand specificity or transcriptional activity. Prostate cancer progression is also associated with increased growth factor production and an altered response to growth factors by prostate cancer cells. The kinase signal transduction cascades initiated by mitogenic growth factors modulate the transcriptional activity of AR and the interaction between AR and AR coactivators. The inhibition of AR activity through mechanisms in addition to androgen ablation, such as modulation of signal transduction pathways, may delay prostate cancer progression.
Highlights
Histological analysis of primary and metastatic prostate cancer indicates that androgen receptor (AR) is expressed throughout prostate cancer progression and in hormone refractory cancer
AR expression is heterogeneous within tumor foci [8, 9, 46], the absence of completely AR-negative hormone refractory tumors suggests that lack of AR expression does not confer a selective advantage to cancer survival or growth
The acquisition of AR mutations that permit AR transcription in response to antiandrogens and/or other endogenous ligands such as adrenal androgens may represent a significant mechanism for the failure of androgen ablation therapy
Summary
Androgen ablation therapy fails, and prostate cancer progresses to a hormone refractory state. Most identified AR mutations from hormone refractory prostate cancer are capable of transcriptional activity (Table 1). These observations suggest that loss of AR function is not a major cause of androgen ablation failure and that AR-negative prostate cancer cells do not have a significant growth or survival advantage. Able clinical and experimental evidence suggests that prostate cancer progression occurs through alteration of the normal androgen axis by dysregulation of AR activity through signal transduction cascades, alteration in the expression of AR coregulators, and mutations of AR that enable it to become transcriptionally active in response to ligands in addition to testosterone and DHT
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