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

Hay CW, McEwan IJ - PLoS ONE (2012)

Bottom Line: 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.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.In addition, the transcriptional outcome of some mutations is dependent upon the androgen receptor responsive element.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.

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.

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Related in: MedlinePlus

Summary of the distribution of the different classes of mutation along the AR protein.
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pone-0032514-g006: Summary of the distribution of the different classes of mutation along the AR protein.

Mentions: This analysis examined 45 single missense mutations detected in PCa with metastasis or high Gleason scores, and which extend along the entire length of the protein. Our sensitive assay system uncovered a previously unidentified category of AR mutation that possesses loss of function at low levels of DHT; converting to a gain of function at physiological levels. Importantly, this type of mutation and virtually all of the other classifications were present in all the domains of the receptor (Fig. 6). The preponderance of PCa-associated mutations display loss of function or activity similar to WT and constitutive gain of function is uncommon. Also, there was a lack of an obvious relationship between the type of AR mutation and the severity of the cancer in which it was detected. Four NTD mutations (G142V, M523V, G524D and M537V) have constitutive transactivational activity clearly demonstrating that the NTD has bearing on regulatory element binding; corroborating earlier work showing that intradomain communication between the NTD and the DBD alters affinity for different response elements [70]. It is noteworthy that all of these mutations contain amino acid substitutions capable of forming intramolecular non-covalent bonds, raising the possibility that ensuing conformational changes induce their transactivational properties. The involvement of mutations in all of the other domains of the AR, not just the DBD e.g. T575A, on regulatory element binding is unequivocal. This may be of particular medical relevance as R629Q, M749I and Q798E in the absence of androgen had loss of function with the hormone response element in GRE2-TATA-Luc but possessed a constitutive gain of function with the AREs in the PSA promoter. Therefore, mutations categorised as having reduced transactivational activity in one analysis, could well be capable of upregulating prostate cancer-related genes.


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

Hay CW, McEwan IJ - PLoS ONE (2012)

Summary of the distribution of the different classes of mutation along the AR protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293822&req=5

pone-0032514-g006: Summary of the distribution of the different classes of mutation along the AR protein.
Mentions: This analysis examined 45 single missense mutations detected in PCa with metastasis or high Gleason scores, and which extend along the entire length of the protein. Our sensitive assay system uncovered a previously unidentified category of AR mutation that possesses loss of function at low levels of DHT; converting to a gain of function at physiological levels. Importantly, this type of mutation and virtually all of the other classifications were present in all the domains of the receptor (Fig. 6). The preponderance of PCa-associated mutations display loss of function or activity similar to WT and constitutive gain of function is uncommon. Also, there was a lack of an obvious relationship between the type of AR mutation and the severity of the cancer in which it was detected. Four NTD mutations (G142V, M523V, G524D and M537V) have constitutive transactivational activity clearly demonstrating that the NTD has bearing on regulatory element binding; corroborating earlier work showing that intradomain communication between the NTD and the DBD alters affinity for different response elements [70]. It is noteworthy that all of these mutations contain amino acid substitutions capable of forming intramolecular non-covalent bonds, raising the possibility that ensuing conformational changes induce their transactivational properties. The involvement of mutations in all of the other domains of the AR, not just the DBD e.g. T575A, on regulatory element binding is unequivocal. This may be of particular medical relevance as R629Q, M749I and Q798E in the absence of androgen had loss of function with the hormone response element in GRE2-TATA-Luc but possessed a constitutive gain of function with the AREs in the PSA promoter. Therefore, mutations categorised as having reduced transactivational activity in one analysis, could well be capable of upregulating prostate cancer-related genes.

Bottom Line: 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.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.In addition, the transcriptional outcome of some mutations is dependent upon the androgen receptor responsive element.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus