title: Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer.
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.
authors.affiliation: Laboratoire de Cancérologie Expérimentale et de Radiobiologie, EA 3430, Université Louis Pasteur de Strasbourg, IRCAD, BP426, Strasbourg Cedex, 67091, France.
authors.forename: A
authors.initials: A
authors.lastname: Monge
authors.forename: M
authors.initials: M
authors.lastname: Jagla
authors.forename: G
authors.initials: G
authors.lastname: Lapouge
authors.forename: S
authors.initials: S
authors.lastname: Sasorith
authors.forename: M
authors.initials: M
authors.lastname: Cruchant
authors.forename: J-M
authors.initials: JM
authors.lastname: Wurtz
authors.forename: D
authors.initials: D
authors.lastname: Jacqmin
authors.forename: J-P
authors.initials: JP
authors.lastname: Bergerat
authors.forename: J
authors.initials: J
authors.lastname: Céraline
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005485:Flutamide / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013256:Steroids / Q000494:pharmacology; D013912:Threonine / Q000235:genetics*
chemical_list: D000726:Androgen Antagonists; D011944:Receptors, Androgen; D013256:Steroids; D013912:Threonine; D005485:Flutamide; D008156:Luciferases