The impact of point mutations in the human androgen receptor: classification of mutations on the basis of transcriptional activity

Colin W Hay, Iain J McEwan

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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.
Original languageEnglish
Article numbere32514
Number of pages13
JournalPloS ONE
Issue number3
Publication statusPublished - 5 Mar 2012


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