title: Profiling human androgen receptor mutations reveals treatment effects in a mouse model of prostate cancer.
abstract: Gain-of-function mutations in the androgen receptor (AR) are found in prostate cancer and are implicated in the failure of hormone therapy. Most studies have emphasized the ligand-binding domain (LBD) where mutations can create promiscuous receptors, but mutations in the NH(2)-terminal transactivation domain have also been found. To assess AR alteration as a mechanism of treatment resistance, a mouse model (h/mAR-TRAMP) was used in which the murine AR coding region is replaced by human sequence and prostate cancer initiated by a transgenic oncogene. Mice received either no treatment, androgen depletion by castration, or treatment with antiandrogens, and 20 AR transcripts were sequenced per end-stage tumor. All tumors expressed several mutant alleles, although most mutations were low frequency. Some mutations that occurred multiple times within the population were differentially located dependent on treatment. Mutations in castrated or antiandrogen-treated mice were widely dispersed but with a prominent cluster in the LBD (amino acids 736-771), whereas changes in intact mice centered near the NH(2)-terminal polymorphic glutamine tract. Functional characterization of selected LBD mutant alleles showed diverse effects on AR activity, with about half of the mutations reducing transactivation in vitro. One receptor, AR-R753Q, behaved in a cell- and promoter-dependent manner, although as a germ-line mutation it causes androgen insensitivity syndrome. This suggests that alleles that are loss of function during development may still activate a subset of AR targets to become gain of function in tumorigenesis. Mutant ARs may thus use multiple mechanisms to evade cancer treatment.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA.
authors.forename: Orla A
authors.initials: OA
authors.lastname: O'Mahony
authors.forename: Mara P
authors.initials: MP
authors.lastname: Steinkamp
authors.forename: Megan A
authors.initials: MA
authors.lastname: Albertelli
authors.forename: Michele
authors.initials: M
authors.lastname: Brogley
authors.forename: Haniya
authors.initials: H
authors.lastname: Rehman
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D011944:Receptors, Androgen