title: Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance.
abstract: The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here, we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated exon 3 and two truncated versions lacking the COOH terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel exon 2b at their 3' end. Functionally, these AR isoforms are constitutively active and promote the expression of endogenous AR-dependent genes, as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, exon 2b-derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR and thus circumvent androgen ablation.
authors.affiliation: Department of Urology and Biochemistry, Mayo Clinical College of Medicine, Rochester, Minnesota, USA. dehm@umn.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Schmidt
authors.forename: Hannelore V
authors.initials: HV
authors.lastname: Heemers
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: C410798:AR protein, human; D018931:Antineoplastic Agents, Hormonal; D020033:Protein Isoforms; D011944:Receptors, Androgen