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Cell Rep. 2017 Aug 15;20(7):1623-1640. doi: 10.1016/j.celrep.2017.07.052.

An Integrated Systems Biology Approach Identifies TRIM25 as a Key Determinant of Breast Cancer Metastasis.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Department of Systems Biology, Columbia University, New York, NY, USA; DarwinHealth, Inc., New York, NY, USA.
3
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Medicine, Weill Cornell Medical Center, New York, NY, USA.
7
Department of Systems Biology, Columbia University, New York, NY, USA. Electronic address: califano@c2b2.columbia.edu.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cellular and Developmental Biology, Weill Cornell Medical College, New York, NY, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: chant@mskcc.org.

Abstract

At the root of most fatal malignancies are aberrantly activated transcriptional networks that drive metastatic dissemination. Although individual metastasis-associated genes have been described, the complex regulatory networks presiding over the initiation and maintenance of metastatic tumors are still poorly understood. There is untapped value in identifying therapeutic targets that broadly govern coordinated transcriptional modules dictating metastatic progression. Here, we reverse engineered and interrogated a breast cancer-specific transcriptional interaction network (interactome) to define transcriptional control structures causally responsible for regulating genetic programs underlying breast cancer metastasis in individual patients. Our analyses confirmed established pro-metastatic transcription factors, and they uncovered TRIM25 as a key regulator of metastasis-related transcriptional programs. Further, in vivo analyses established TRIM25 as a potent regulator of metastatic disease and poor survival outcome. Our findings suggest that identifying and targeting keystone proteins, like TRIM25, can effectively collapse transcriptional hierarchies necessary for metastasis formation, thus representing an innovative cancer intervention strategy.

KEYWORDS:

ARACNe; EFP; MARINa; TRIM25; VIPER; breast; cancer; metastasis; transcription

Comment in

PMID:
28813674
PMCID:
PMC5985663
DOI:
10.1016/j.celrep.2017.07.052
[Indexed for MEDLINE]
Free PMC Article

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