title: 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.
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Cancer Biology, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Lindsey Ulkus
authors.initials: LU
authors.lastname: Rodrigues
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Leah
authors.initials: L
authors.lastname: Rider
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Cera
authors.initials: C
authors.lastname: Nieto
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Lina
authors.initials: L
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Anis
authors.initials: A
authors.lastname: Karimpour-Fard
authors.affiliation: Department of Pathology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Lucia
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Cancer Biology, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Pathology, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Adela
authors.initials: A
authors.lastname: Cimic
authors.affiliation: Department of Pathology, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Sirintrapun
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Nolley
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Colton
authors.initials: C
authors.lastname: Pac
authors.affiliation: Center for Genetic Epidemiology, Fudan University, Shanghai, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.affiliation: Center for Cancer Genomics, Wake Forest University, Winston-Salem, North Carolina. Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Cancer Genomics, Wake Forest University, Winston-Salem, North Carolina. Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. scott.cramer@ucdenver.edu.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
mesh_terms: D000818:Animals; D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004265:DNA Helicases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D015820:Cadherins; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C080359:CHD1 protein, human