Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer.
Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen-dependent to androgen-independent growth. We use a yeast-based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c-terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.
Céraline
Jocelyn
J
Laboratoire de Cancérologie Expérimentale et de Radiobiologie-EA/ULP 3430, IRCAD, Strasbourg, France. jocelyn.ceraline@ircad.u-strasbg.fr
Cruchant
Marion D
MD
Erdmann
Eva
E
Erbs
Philippe
P
Kurtz
Jean-Emmanuel
JE
Duclos
Brigitte
B
Jacqmin
Didier
D
Chopin
Dominique
D
Bergerat
Jean-Pierre
JP
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000556:secondary; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics*; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D011944:Receptors, Androgen