Abstract.
Missense mutations in the androgen receptor (AR) contribute to the failure of hormonal therapy for prostate cancer (PCa), but the underlying molecular bases remain uncharacterized. Here, we describe a new AR variant found in a hormone-refractory metastatic PCa, in which threonine 575 in the DNA binding domain, and threonine 877 in the ligand-binding domain, were both replaced by an alanine. Using gene reporter assays, we demonstrate that the T575A mutation weakened transcriptional activity from promoters containing AR-specific responsive elements, while activity from promoters with AR-non-specific elements was enhanced. Data from gel shift experiments revealed a preferential binding of the T575A mutant to AR-non-specific motifs. We demonstrate that the two mutations T575A and T877A cooperate to confer new functional properties on the AR, and that the mutant AR functions simultaneously as a promiscuous AR due to the T877A mutation, and an unfaithful AR due to the T575A mutation.
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Received 6 October 2005; received after revision 16 November 2005; accepted 8 December 2005
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Monge, A., Jagla, M., Lapouge, G. et al. Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer. Cell. Mol. Life Sci. 63, 487–497 (2006). https://doi.org/10.1007/s00018-005-5471-y
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DOI: https://doi.org/10.1007/s00018-005-5471-y