Related Experiment Video

Updated: Jul 23, 2025

Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
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Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material

Published on: August 1, 2018

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Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

Zhe Jiang1, YoungJun Ju1, Amjad Ali1

  • 1Toronto General Research Institute - University Health Network, 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON, M5G 1L7, Canada.

Nature Communications
|July 18, 2023
PubMed

Insights

Understanding breast cancer metastasis drivers is key. This study identifies shared and distinct oncogenic pathways in primary tumors versus metastases, revealing new therapeutic targets to prevent spread.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Metastatic breast cancer remains a leading cause of cancer death globally.
  • The specific genetic drivers promoting primary tumor growth versus metastasis are not fully understood.
  • Retinoblastoma 1 (RB1) is frequently inactivated in breast cancer, but its role in metastasis is debated.

Purpose of the Study:

  • To investigate the distinct and shared oncogenic drivers of primary breast tumors and metastases.
  • To identify potential therapeutic targets for preventing breast cancer metastasis.
  • To correlate findings from mouse models with human clinical data.

Main Methods:

  • Mammary-specific transposon mutagenesis screens in female mice.
  • Inclusion of loss-of-function Rb mutations to model breast cancer.
  • Analysis of gene-centric common insertion sites (gCIS) in primary tumors and metastases.
  • Pathway analysis of four human clinical cohorts with paired primary tumors and metastases.

Main Results:

  • Identified distinct gene sets enriched in primary tumors, metastases, or both.
  • Discovered a MET-RAS network common to both primary tumors and metastases.
  • Uncovered metastasis-specific signaling hubs including Rho-signaling, Ubiquitination, and RNA-processing.
  • Human data confirmed subtype-specific drivers, with shared (e.g., RB1, TP53, MET, RAS), primary-enriched (e.g., EGFR, TGFβ, STAT3), and metastasis-enriched (e.g., RHO, PI3K) pathways.
  • Inhibitors targeting RB1 deficiency or MET/RHO signaling demonstrated synergistic effects in blocking migration and inducing cell death.

Conclusions:

  • Breast cancer metastasis is driven by a distinct set of oncogenic signaling pathways separate from those driving primary tumor growth.
  • Targeting shared oncogenic drivers (MET-RAS) and metastasis-specific drivers (Rho-signaling) offers a promising strategy to prevent or treat metastatic breast cancer.
  • Therapeutic strategies should differentiate between drivers of primary tumor growth and those promoting metastasis for optimal efficacy.

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