Unknown,Transcriptomics,Genomics,Proteomics

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Prostate specific Pten deletion, Pten-Smad4 deletion, and Pten-p53 deletion

ABSTRACT: We used microarrays to detail the global gene expression and identified differentially expressed gene list between wild-type anterior prostates and Ptenpc-/- anterior prostates, Ptenpc-/-Smad4pc-/- and Ptenpc-/- anterior prostates, Ptenpc-/-p53pc-/- and Ptenpc-/- anterior prostates at 15 weeks of age. Prostate-specific Pten deletion (Ptenpc-/-) results in prostate intraepithelial neoplasia (PIN) which, following a long latency, can progress to high-grade adenocarcinoma, albeit with minimally invasive and metastatic features. To understand this feeble progression phenotype, we conducted transcriptome comparison of five Ptenpc-/- PIN relative to three wild-type anterior prostate. Moreover, Ptenpc-/-Smad4pc-/- progress to metastasis, while Ptenpc-/-p53pc-/- not progress to metastasis. To understand this phenotype difference, we conducted transcriptome comparison of five Ptenpc-/-Smad4pc-/-to five Ptenpc-/- prostate tumor, and three Ptenpc-/-p53pc-/- to five Ptenpc-/- tumor.

ORGANISM(S): Mus musculus

SUBMITTER: Zhihu Ding

PROVIDER: E-GEOD-25140 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Prostate specific Pten deletion, Pten-Smad4 deletion, and Pten-p53 deletion

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