Coordinate Loss of MAP3K7 and CHD1 Promotes Aggressive Prostate Cancer

被引：74

作者：

Rodrigues, Lindsey Ulkus ^{[1
,2
]}

Rider, Leah ^{[1
]}

Nieto, Cera ^{[1
]}

Romero, Lina ^{[1
]}

Karimpour-Fard, Anis ^{[1
]}

Loda, Massimo ^{[3
]}

Lucia, M. Scott ^{[4
]}

Wu, Min ^{[1
]}

Shi, Lihong ^{[2
]}

Cimic, Adela ^{[5
]}

Sirintrapun, S. Joseph ^{[5
]}

Nolley, Rosalie ^{[6
]}

Pac, Colton ^{[1
]}

Chen, Haitao ^{[7
]}

Peehl, Donna M. ^{[6
]}

Xu, Jianfeng ^{[8
,9
]}

Liu, Wennuan ^{[8
,9
]}

Costello, James C. ^{[1
]}

Cramer, Scott D. ^{[1
]}

机构：

[1] Univ Colorado, Dept Pharmacol, Aurora, CO 80045 USA

[2] Wake Forest Univ, Dept Canc Biol, Winston Salem, NC 27109 USA

[3] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA

[4] Univ Colorado, Dept Pathol, Aurora, CO 80045 USA

[5] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27103 USA

[6] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA

[7] Fudan Univ, Ctr Genet Epidemiol, Shanghai 200433, Peoples R China

[8] Wake Forest Univ, Ctr Canc Genom, Winston Salem, NC 27109 USA

[9] Wake Forest Univ, Ctr Genom & Personalized Med Res, Winston Salem, NC 27109 USA

来源：

CANCER RESEARCH | 2015年 / 75卷 / 06期

关键词：

MEDIATED CELL-ADHESION; I-KAPPA-B; MESENCHYMAL TRANSITION; E-CADHERIN; KINASE TAK1; EXPRESSION; CARCINOMA; NEUROENDOCRINE; ACTIVATION; DELETION;

D O I：

10.1158/0008-5472.CAN-14-1596

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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(dcl)CHD1(dcl)) 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.

引用

页码：1021 / 1034

页数：14

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