Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy.
To identify regulatory drivers of prostate cancer malignancy, we have assembled genome-wide regulatory networks (interactomes) for human and mouse prostate cancer from expression profiles of human tumors and of genetically engineered mouse models, respectively. Cross-species computational analysis of these interactomes has identified FOXM1 and CENPF as synergistic master regulators of prostate cancer malignancy. Experimental validation shows that FOXM1 and CENPF function synergistically to promote tumor growth by coordinated regulation of target gene expression and activation of key signaling pathways associated with prostate cancer malignancy. Furthermore, co-expression of FOXM1 and CENPF is a robust prognostic indicator of poor survival and metastasis. Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer.
Department of Urology, Columbia University Medical Center, New York, NY 10032.|Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Barcelona, Spain 08907.
Alvaro
A
Aytes
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
Antonina
A
Mitrofanova
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
Celine
C
Lefebvre
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
Mariano J
MJ
Alvarez
Department of Pathology, Icahn School of Medicine at Mount Sinai New York, NY 10029.
Mireia
M
Castillo-Martin
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.|Department of Statistics, Columbia University, New York, NY 10027.
Tian
T
Zheng
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
James A
JA
Eastham
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Anuradha
A
Gopalan
The University of Michigan Ann Arbor, MI 48109, and the Brady Urological Institute at the Johns Hopkins School of Medicine, Baltimore, MD 21231.
Kenneth J
KJ
Pienta
Department of Urology, Columbia University Medical Center, New York, NY 10032.|Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.|Department of Medicine, Columbia University Medical Center, New York, NY 10032.|Department of Genetics & Development, Columbia University Medical Center, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.
Michael M
MM
Shen
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.|Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.
Andrea
A
Califano
Department of Urology, Columbia University Medical Center, New York, NY 10032.|Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032.
Cory
C
Abate-Shen
D000465:Algorithms; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
D002868:Chromosomal Proteins, Non-Histone; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008840:Microfilament Proteins; C094772:centromere protein F