Dataset Information

Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer.

ABSTRACT: Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development.

SUBMITTER: Rodrigues LU

PROVIDER: S-EPMC4531265 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer.

Rodrigues Lindsey Ulkus LU Rider Leah L Nieto Cera C Romero Lina L Karimpour-Fard Anis A Loda Massimo M Lucia M Scott MS Wu Min M Shi Lihong L Cimic Adela A Sirintrapun S Joseph SJ Nolley Rosalie R Pac Colton C Chen Haitao H Peehl Donna M DM Xu Jianfeng J Liu Wennuan W Costello James C JC Cramer Scott D SD

Cancer research 20150301 6

Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were signif ...[more]

PMID: 25770290

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Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl and shMAP3K7/shCHD1 was used to identify transcriptome changes resulting from loss of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.

Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify transcriptome changes resulting from loss of each of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.

Dataset Information

Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer.

Publications

Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer.

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