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.

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.

Similar Datasets

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