Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance and response in castration-resistant prostate cancer

ABSTRACT: aCGH experiment on cell-free DNA collected from the plasma of patients with castration-resistant prostate cancer. No replicates. castration-resistant prostate cancer vs male reference DNA

ORGANISM(S): Homo sapiens

SUBMITTER: Shawn Anderson

PROVIDER: E-GEOD-61134 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.

Azad Arun A AA Volik Stanislav V SV Wyatt Alexander W AW Haegert Anne A Le Bihan Stephane S Bell Robert H RH Anderson Shawn A SA McConeghy Brian B Shukin Robert R Bazov Jenny J Youngren Jack J Paris Pamela P Thomas George G Small Eric J EJ Wang Yuzhuo Y Gleave Martin E ME Collins Colin C CC Chi Kim N KN

Clinical cancer research : an official journal of the American Association for Cancer Research 20150223 10

<h4>Purpose</h4>Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.<h4>Experimental design</h4>Plasma was collected from 62 mCRPC patient ...[more]

PMID: 25712683

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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

Dataset Information

Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance and response in castration-resistant prostate cancer

Publications

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.

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