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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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:The androgen receptor (AR) is an androgen-activated nuclear receptor. The androgen signaling axis is critical in all stages of prostate cancer, although the mechanism by which it contributes to tumorigenesis remains unclear. Mutations in the AR have been detected in prostate tumors; one such mutant, E231G, exhibits increased ligand sensitivity in the presence of specific cofactors. Mice with prostate-specific expression of AR-E231G invariably develop prostatic intraepithelial neoplasia (PIN) by 12 weeks, and metastatic prostate cancer by 52 weeks. To determine a potential mechanism of AR-driven tumorigenesis in AR-E231G mice, we compared gene expression profiles in prostates of 12 week old AR-E231G mice with another AR-variant mouse strain (AR-T857A) that does not develop tumors. Pathway classification of the 132 candidate genes differentially expressed in AR-E231G mouse prostates compared to AR-T857A mouse prostates revealed enrichment for groups important in prostate cancer, including “cancer,” “fatty acid metabolism” and “cell cycle” pathways. Two genes significantly upregulated in the AR-E231G model were Adm and Cited1. siRNA suppression of ADM and CITED1 expression by up to 63% and 79%, respectively, in LNCaP human prostate cancer cells, resulted in an approximate 1.8-fold increase in cell death. Cell proliferation was reduced by 35% when CITED1 mRNA expression was suppressed, but not significantly altered by ADM suppression. A gene signature set derived from this model was able to distinguish between primary Gleason grade 3 and Gleason grade 4 tumors (p=0.04237), and between human non-malignant and cancerous prostate in a test (p=0.02352) and validation cohort (p=7.53x10-9), highlighting the relevance of the AR-E231G model to the human disease. RNA was extracted from ventral prostate tissue from 12-week old AR-E231G and AR-T857A mice in FVB background. Pooled RNA from 3 mice per genotype were extracted using the RNeasy kit (Qiagen, Germantown, MD, USA), and 10 µg RNA was hybridized to a total of 2 Affymetrix Mouse Genome 430 2.0 chip® microarrays. Microarray data was normalized by Robust Multiarray Averaging. Probes with expression changes were identified using a fold-change cut-off of log1.5. Normalized microarray data was analysed using Ingenuity Pathways Analysis (IPA, Redwood City, CA, USA).

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