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

Overview

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.

publication date

  • August 15, 2017

Research

keywords

  • Breast Neoplasms
  • Gene Expression Regulation, Neoplastic
  • Lung Neoplasms
  • Neoplasm Proteins
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Identity

PubMed Central ID

  • PMC5985663

Scopus Document Identifier

  • 85027842034

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.07.052

PubMed ID

  • 28813674

Additional Document Info

volume

  • 20

issue

  • 7