Dataset Information

Nkx3.1 controls the DNA repair response in the mouse prostate.

ABSTRACT:

Background

The human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2-ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.

Methods

Using both drug-induced DNA damage and ?-irradiation, we assayed expression of ?-histone 2AX at time points up to 24?hr after induction of DNA damage.

Results

We demonstrated that expression of Nkx3.1 influenced both the timing and magnitude of the DNA damage response in the prostate.

Conclusions

Nkx3.1 affects the DNA damage response in the murine prostate and is haploinsufficient for this phenotype.

SUBMITTER: Zhang H

PROVIDER: S-EPMC4738428 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Nkx3.1 controls the DNA repair response in the mouse prostate.

Zhang Hailan H Zheng Tian T Chua Chee Wai CW Shen Michael M Shen Michael M Gelmann Edward P EP

The Prostate 20151210 4

<h4>Background</h4>The human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2-ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.<h4>Methods</h4>Using both drug-induced DNA damage and γ-irradiation, we assayed expression of γ-histone 2AX at time points u ...[more]

PMID: 26660523

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Project description:BackgroundAlthough men on active surveillance for prostate cancer (PCa) may benefit from intervention with 5α-reductase inhibitors (5-ARIs), it has not been resolved whether 5-ARIs are effective for delaying disease progression and, if so, whether specific patients are more likely to benefit.ObjectiveTo identify molecular features predictive of patient response to 5-ARIs.Design, setting, and participantsNkx3.1 mutant mice, a model of early-stage PCa, were treated with the 5-ARI finasteride, and histopathological and molecular analyses were performed. Cross-species computational analyses were used to compare expression profiles for treated mice with those of patients who had received 5-ARIs before prostatectomy.InterventionFinasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively.Outcome measurements and statistical analysisEndpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses.Results and limitationsFinasteride treatment of Nkx3.1 mutant mice resulted in a significant reduction in prostatic intraepithelial neoplasia (PIN), as evident from histopathological and expression profiling analyses. Cross-species computational analysis comparing finasteride-treated mice with two independent 5-ARI-treated patient cohorts showed that reduced NKX3.1 expression is predictive of response to 5-ARI. A limitation of the study is that these retrospective human cohorts have relatively few patients with limited clinical outcome data. Future prospective clinical trials are needed to validate whether stratifying patients on the basis of NKX3.1 expression improves the benefit of 5-ARIs during active surveillance.ConclusionsThis co-clinical study implicates NKX3.1 status as a predictor of response to 5-ARIs, and suggests that molecular features, including NKX3.1 expression, may help to identify PCa patients most likely to benefit from 5-ARIs during active surveillance.Patient summaryThe aim of precision cancer prevention is to tailor interventions on the basis of individualized patient characteristics. We propose that patients with low NKX3.1 expression are optimal candidates for intervention with 5α-reductase inhibitors as an adjunct to active surveillance.

Project description:Gene fusions involving ETS family transcription factors (mainly TMPRSS2-ERG and TMPRSS2-ETV1 fusions) have been found in ~50% of human prostate cancer cases. Although expression of TMPRSS2-ERG or TMPRSS2-ETV1 fusion alone is insufficient to initiate prostate tumorigenesis, they appear to sensitize prostate epithelial cells for cooperation with additional oncogenic mutations to drive frank prostate adenocarcinoma. To search for such ETS-cooperating oncogenic events, we focused on a well-studied prostate tumor suppressor NKX3.1, as loss of NKX3.1 is another common genetic alteration in human prostate cancer. Previous studies have shown that deletions at 8p21 (harboring NKX3.1) and 21q22 (resulting in TMPRSS2-ERG fusion) were both present in a subtype of prostate cancer cases, and that ERG can lead to epigenetic silencing of NKX3.1 in prostate cancer cells, whereas NKX3.1 can in turn negatively regulate TMPRSS2-ERG fusion expression via suppression of the TMPRSS2 promoter activity. We recently generated knockin mouse models for TMPRSS2-ERG and TMPRSS2-ETV1 fusions, utilizing the endogenous Tmprss2 promoter. We crossed these knockin models to an Nkx3.1 knockout mouse model. In Tmprss2-ERG;Nkx3.1+/- (or -/-) male mice, although we observed a slight but significant upregulation of Tmprss2-ERG fusion expression upon Nkx3.1 loss, we did not detect any significant cooperation between these two genetic events to enhance prostate tumorigenesis in vivo. Furthermore, retrospective analysis of a previously published human prostate cancer dataset revealed that within ERG-overexpressing prostate cancer cases, NKX3.1 loss or deletion did not predict biochemical relapse after radical prostatectomy. Collectively, these data suggest that although TMPRSS2-ERG fusion and loss of NKX3.1 are among the most common mutational events found in prostate cancer, and although each of them can sensitize prostate epithelial cells for cooperating with other oncogenic events, these two events themselves do not appear to cooperate at a significant level in vivo to enhance prostate tumorigenesis.

Dataset Information

Nkx3.1 controls the DNA repair response in the mouse prostate.

Background

Methods

Results

Conclusions

Publications

Nkx3.1 controls the DNA repair response in the mouse prostate.

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