Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression in gastrocnemius muscle from DNA binding-dependent androgen receptor knockout male mice

ABSTRACT: Gene expression profiles were examined in DNA binding-dependent androgen receptor knockout (DBD-ARKO) and WT male mice to identify genes regulated by the AR. DBD-ARKO mice have an in-frame deletion of exon 3 of the AR.

ORGANISM(S): Mus musculus

SUBMITTER: Helen MacLean

PROVIDER: E-MTAB-597 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice.

MacLean Helen E HE Chiu W S Maria WS Notini Amanda J AJ Axell Anna-Maree AM Davey Rachel A RA McManus Julie F JF Ma Cathy C Plant David R DR Lynch Gordon S GS Zajac Jeffrey D JD

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20080407 8

To identify mechanisms of anabolic androgen action in muscle, we generated male and female genomic androgen receptor (AR) knockout (ARKO) mice, and characterized muscle mass, contractile function, and gene expression. Muscle mass is decreased in ARKO males, but normal in ARKO females. The levator ani muscle, which fails to develop in normal females, is also absent in ARKO males. Force production is decreased from fast-twitch ARKO male muscle, and slow-twitch muscle has increased fatigue resistan ...[more]

PMID: 18390925

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Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.

Dataset Information

Gene expression in gastrocnemius muscle from DNA binding-dependent androgen receptor knockout male mice

Publications

Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice.

Similar Datasets

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