Dataset Information

SPOP mutation - SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

ABSTRACT: Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.

OTHER RELATED OMICS DATASETS IN: PRJNA374556

INSTRUMENT(S): LTQ

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Prostate Gland

SUBMITTER: Anton Poliakov

LAB HEAD: Anton Poliakov

PROVIDER: PXD005309 | Pride | 2017-03-20

REPOSITORIES: Pride

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Publications

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling.

Blattner Mirjam M Liu Deli D Robinson Brian D BD Huang Dennis D Poliakov Anton A Gao Dong D Nataraj Srilakshmi S Deonarine Lesa D LD Augello Michael A MA Sailer Verena V Ponnala Lalit L Ittmann Michael M Chinnaiyan Arul M AM Sboner Andrea A Chen Yu Y Rubin Mark A MA Barbieri Christopher E CE

Cancer cell 20170301 3

Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP dr ...[more]

PMID: 28292441

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Project description:Aberrant activation of androgen receptor (AR)-dependent transcriptional programs is a hallmark of human prostate cancers. At the molecular level, ligand-mediated AR activation is coordinated through spatial and temporal protein-protein interactions (PPIs) involving AR-interacting proteins, which we designate the “AR-interactome”. Despite many years of research, the ligand-sensitive protein complexes involved in ligand-mediated AR activation in prostate-tumor cells has not been clearly defined. Here, we describe the development, characterization, and utilization of a novel human LNCaP prostate-tumor cell line, N-AR, which stably expresses wild-type AR containing the streptavidin-binding peptide epitope tagged at its N-terminus (SBP-AR). A bioanalytical workflow involving streptavidin-chromatography and label-free quantitative mass spectrometry was used to identify SBP-AR and associated ligand-sensitive proteins/protein complexes functionally linked to AR activation in the cytosol of N-AR cells. Functional studies verified that ligand-sensitive streptavidin-copurified proteins encoded modulators of AR-mediated transcription, suggesting that these novel proteins were putative SBP-AR-interacting proteins in N-AR cells. This was supported by biochemical associations between recombinant SBP-AR and the ligand-sensitive COPI retrograde trafficking complex in vitro. Extensive biochemical and molecular experiments showed that the COPI-retrograde complex regulates ligand-mediated AR transcriptional activation through the mobilization of Golgi-localized ARA160 coactivator into the nuclear compartment of prostate-tumor cells. Collectively, this study provides a bioanalytical strategy to validate the AR-interactome and define novel AR-interacting proteins involved in ligand-mediated AR activation in prostate-tumor cells. Moreover, we describe a cellular system to study how compartment-specific AR-interacting proteins influence AR activation and contribute to aberrant AR-dependent transcription that underlies the majority of human prostate cancers.

Dataset Information

SPOP mutation - SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Publications

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling.

Similar Datasets

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