Abstract
Androgen receptor mediated signaling drives prostate cancer cell growth and survival. Mutations within the receptor occur infrequently in prostate cancer prior to hormonal therapy but become prevalent in incurable androgen independent and metastatic tumors. Despite the determining role played by the androgen receptor in all stages of prostate cancer progression, there is a conspicuous dearth of comparable data on the consequences of mutations. In order to remedy this omission, we have combined an expansive study of forty five mutations which are predominantly associated with high Gleason scores and metastatic tumors, and span the entire length of the receptor, with a literature review of the mutations under investigation. We report the discovery of a novel prevalent class of androgen receptor mutation that possesses loss of function at low levels of androgen yet transforms to a gain of function at physiological levels. Importantly, mutations introducing constitutive gain of function are uncommon, with the majority of mutations leading to either loss of function or no significant change from wild-type activity. Therefore, the widely accepted supposition that androgen receptor mutations in prostate cancer result in gain of function is appealing, but mistaken. In addition, the transcriptional outcome of some mutations is dependent upon the androgen receptor responsive element. We discuss the consequences of these findings and the role of androgen receptor mutations for prostate cancer progression and current treatment options.
Highlights
Prostate cancer (PCa) is the second most frequently diagnosed cancer of men [1] with the most recent figures from 2010 showing annual deaths of 10,168 in the UK [2] and 32,050 deaths in the US [3] reflecting its prominence as the second leading cause of cancer death in men in Western nations.Androgen signaling, which is mediated through the androgen receptor (AR), directs development, differentiation and carcinogenesis of the prostate gland [4,5]
Androgen receptor mutations under study Inspection of the Androgen Receptor Gene Mutations Database [39] and the literature reveals that prostate cancer-associated single missense mutations occur in the different domains of the AR with relatively comparable frequencies
The investigation reported here has focused on 45 single missense mutations detected in prostate cancer (PCa) with metastasis or high Gleason scores, and which extend along the entire length of the protein thereby encompassing all of the different functional domains
Summary
Prostate cancer (PCa) is the second most frequently diagnosed cancer of men [1] with the most recent figures from 2010 showing annual deaths of 10,168 in the UK [2] and 32,050 deaths in the US [3] reflecting its prominence as the second leading cause of cancer death in men in Western nations.Androgen signaling, which is mediated through the androgen receptor (AR), directs development, differentiation and carcinogenesis of the prostate gland [4,5]. Androgen signaling subsequently plays a central role in cancer cell growth and survival [6,7]. Androgen ablation through blocking testicular production of androgens, and inhibition of AR function with antagonists constitute the principal systemic treatments for metastatic disease [5,6,8]. Initially efficacious, such therapies fail to provide a lasting cure and the tumor invariably escapes with progression to an exoteric-androgen independent (AI) state [9] which almost invariably leads to death. Hormone refractory tumors continue to express functional AR which plays a critical role in AI cells [10,11] where it drives a different transcriptome compared to androgen-sensitive cells [12]
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