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Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Ipshita Nandi1,2, Harvey W Smith1, Virginie Sanguin-Gendreau1,2

  • 1Rosalind and Morris Goodman Cancer Institute and.

The Journal of Clinical Investigation
|February 16, 2023
PubMed

Insights

The tyrosine kinase c-Src activates forkhead box M1 (FOXM1), a cell cycle regulator, promoting aggressive breast cancer. Targeting this c-Src/FOXM1 pathway halts tumor growth and metastasis in luminal B breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • c-Src tyrosine kinase activation is linked to breast cancer progression and poor patient outcomes.
  • The precise mechanisms by which c-Src drives breast cancer remain incompletely understood.
  • Forkhead box M1 (FOXM1) is a critical transcriptional regulator of the cell cycle.

Purpose of the Study:

  • To elucidate the role of c-Src in regulating FOXM1 activity in breast cancer.
  • To investigate the c-Src-FOXM1 regulatory network in luminal B breast cancer.
  • To explore therapeutic strategies targeting the c-Src-FOXM1 axis.

Main Methods:

  • Utilized a genetically engineered mouse model of luminal B breast cancer.
  • Investigated c-Src phosphorylation of FOXM1 and its effect on nuclear localization.
  • Employed genetic approaches and small molecules to target the FOXM1 protein.

Main Results:

  • c-Src deletion abrogated FOXM1 activity in a luminal B breast cancer model.
  • c-Src phosphorylates FOXM1 on tyrosine residues, enhancing its nuclear localization and target gene expression.
  • A positive feedback loop between c-Src and FOXM1 was identified, driving proliferation.
  • Targeting FOXM1 induced cell-cycle arrest, apoptosis, and reduced tumor progression and metastasis.
  • A positive correlation between FOXM1 and c-Src expression was observed in human breast cancer.

Conclusions:

  • The c-Src-FOXM1 regulatory network is a key driver of aggressive luminal B breast cancer.
  • FOXM1 expression and its target genes are associated with poor outcomes in luminal B breast cancer.
  • This c-Src-FOXM1 axis represents a potential therapeutic vulnerability in aggressive breast cancers.
Keywords:
Breast cancerCell cycleMouse modelsOncologyTherapeutics

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