Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR.
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The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response, Pten-/-epithelia continue to proliferate yielding locally invasive primary tumor pathology. That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described Pten-/- tumor cell lines derived from both from hormone intact (E4, E8) and castrated Pten mutants (cE1, cE2) followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants (mAR-Va, b, c). Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.
PloS one. 2015 Jul 21*** epublish ***
Mengmeng Liang, Helty Adisetiyo, Xiuqing Liu, Ren Liu, Parkash Gill, Pradip Roy-Burman, Jeremy O Jones, David J Mulholland
Icahn School of Medicine at Mount Sinai, New York, New York, United States of America. , Children's Hospital of Los Angeles, Los Angeles, California, United States of America. , St. Luke's Hospital, Internal medicine resident, Chesterfield, Missouri, United States of America. , Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America. , Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America. , Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, United States of America. , Beckman Research Institute, City of Hope, Duarte, California, United States of America. , Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.