Unknown,Transcriptomics,Genomics,Proteomics

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AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.

ABSTRACT: Androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed as one of the most important mechanisms underlying failure of therapy. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds more credence to this idea. Expression of AR-Vs in metastases portends a rapid progression of the tumor. However, the precise role of the AR-Vs in CRPC still remains unknown. ARv567es is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter-driven ARv567es transgenic mouse, Pb-ARv567es, to evaluate the role of ARv567es in both autonomous prostate growth and progression to CRPC. We found that expression of ARv567es in the prostate results in epithelial hyperplasia by 16 weeks and invasive adenocarcinoma is evident by 1 year of age. The underlying genetic cellular events involved a cell cycle-related transcriptome and differential expression of a spectrum of genes that are critical for tumor initiation and progression. These findings indicate that ARv567es could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-ARv567es mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined. Custom Agilent 44K whole mouse genome expression oligonucleotide microarrays were used to profile prostate tissue from probasin (Pb) promoter-driven ARv567es transgenic mice and control littermates. Total RNA was isolated and amplified prior to hybridization against a common reference pool of normal adult mouse tissues.

ORGANISM(S): Mus musculus

SUBMITTER: Ilsa Coleman

PROVIDER: E-GEOD-61303 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.

Liu Gang G Sprenger Cynthia C Sun Shihua S Epilepsia Kathryn Soriano KS Haugk Kathleen K Zhang Xiaotun X Coleman Ilsa I Nelson Peter S PS Plymate Stephen S

Neoplasia (New York, N.Y.) 20130901 9

Androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed as one of the most important mechanisms underlying failure of therapy. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds more credence to this idea. Expression of AR-Vs ...[more]

PMID: 24027426

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Project description:Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2M-bM-^@M-^S3-fold and the other 4M-bM-^@M-^S5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequencing (seq) to identify AR-binding sites (ARBSs). We found that the number of ARBSs and the AR-binding strength were positively associated with the level of AR when cells were stimulated with low concentrations of androgens. In cells overexpressing AR, the chromatin binding of the receptor took place in 100-fold lower concentration of the ligand than in control cells. We conM-oM-,M-^Armed the association of AR level and chromatin binding in two PC xenografts, one containing AR gene ampliM-oM-,M-^Acation with high AR expression, and the other with low expression. By combining the ChIP-seq and expression proM-oM-,M-^Aling, we identiM-oM-,M-^Aed AR target genes that are upregulated in PC. Of them, the expression of ZWINT, SKP2 (S-phase kinase-associated protein 2 (p45)) and FEN1 (M-oM-,M-^Bap structure-speciM-oM-,M-^Ac endonuclease 1) was demonstrated to be increased in CRPC, while the expression of SNAI2 was decreased in both PC and CRPC. FEN1 protein expression was also associated with poor prognosis in prostatectomy-treated patients. Finally, the knock-down of FEN1 with small interfering RNA inhibited the growth of LNCaP cells. Our data demonstrate that the overexpression of AR sensitizes the receptor binding to chromatin, thus, explaining how AR signaling pathway is reactivated in CRPC cells. Examination of AR binding with 9 cell line samples + control and 2 xenograft samples + control. ChIPseq with AR antibody in 3 different LNCaP derivative cell lines overexpressing AR upon treatment with different androgen concentrations and 2 different tumor xenografts expressing different AR levels.

Dataset Information

AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.

Publications

AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.

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