Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets

ABSTRACT: MicroRNA (miRNA) expression profiles were generated from prostate epithelial sub-populations, enriched from patient-derived benign prostatic hyperplasia (BPH, n=5), Gleason 7 treatment naÃ¯ve prostate cancer (PCa, n=5) and castration-resistant prostate cancer (CRPC, n=3). Microarray expression was validated in an independent patient cohort (n=10). The analyses show that miRNA expression in epithelial sub-populations (e.g. stem cells) clustered together, irrespective of pathological status. We also discovered concordance between the miRNA expression profiles of unfractioned CRPCs, human embryonic stem cells (SCs), and prostate epithelial SCs (both, benign and malignant). miR-548c-3p was chosen as a candidate miRNA from this group to explore its utility as a CRPC biomarker and/or therapeutic target. Overexpression of miR-548c-3p was confirmed in cancer SCs (8-fold, p<0.05) and unfractionated CRPCs (1.8-fold, p<0.05). Enforced overexpression of miR-548c-3p in differentiated cells induced stem-like properties (p 0.01) and radioresistance (p<0.01). Re-analyses of published studies further revealed that miR-548c-3p is significantly overexpressed in CRPC (p<0.05) and is associated with poor recurrence-free survival (p<0.05), suggesting that miR-548c-3p is a functional biomarker for prostate cancer aggressiveness. Our results validate the prognostic and therapeutic relevance of miRNAs for advanced prostate cancer management, whilst demonstrating that resolving cell-type and differentiation-specific differences is essential to obtain clinical relevant miRNA expression profiles. There are 42 samples in total: 15 benign prostatic hyperplasia, 15 prostate cancers, 9 treatment-resistant prostate cancer. There are stem cells, transit amplifying cells and committed basal cells dissected from each sample. Three PrEC samples of each three cell types can be used as reference.

ORGANISM(S): Homo sapiens

SUBMITTER: Antti YlipÃ¤Ã¤

PROVIDER: E-GEOD-59156 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).

Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS‑ prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.

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MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets

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