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Intramitochondrial Src kinase links mitochondrial dysfunctions and aggressiveness of breast cancer cells

Marie-Ange Djeungoue-Petga1,2, Olivier Lurette1,2, Stéphanie Jean1,2

  • 1Canada Research Chair in Mitochondrial Signaling and Physiopathology, Moncton, NB, Canada.

Cell Death & Disease
|December 11, 2019
PubMed

Insights

Mitochondrial Src (mtSrc) kinase activity is elevated in triple-negative breast cancer, driving cancer aggressiveness by impairing mitochondrial function and DNA replication. Targeting mtSrc may offer novel therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Mitochondrial Biology

Background:

  • Src kinase is frequently overexpressed in breast cancer, and its inhibition is a therapeutic target.
  • Mitochondrial dysfunction is implicated in various cancer types.
  • The specific role of mitochondrial Src (mtSrc) in breast cancer remains largely unexplored.

Purpose of the Study:

  • To investigate the specific impact of mtSrc on breast cancer cell behavior.
  • To determine if mtSrc activity differs across breast cancer subtypes.
  • To elucidate the molecular mechanisms by which mtSrc influences mitochondrial function and cancer progression.

Main Methods:

  • Comparative analysis of mtSrc activity in different breast cancer subtypes.
  • Experimental manipulation of mtSrc expression in breast cancer cells.
  • Assessment of mitochondrial parameters including mtDNA levels, membrane potential, and respiration.
  • Proteomic analysis to identify mtSrc targets within mitochondria.

Main Results:

  • mtSrc activity was significantly higher in triple-negative breast cancer cells.
  • Overexpression of mtSrc led to decreased mtDNA levels, reduced mitochondrial membrane potential, and impaired cellular respiration.
  • These mitochondrial alterations correlated with decreased cellular viability, a shorter cell cycle, and increased invasive capacity.
  • Proteomic analysis identified the mitochondrial single-stranded DNA-binding protein as a key target of mtSrc.

Conclusions:

  • mtSrc plays a critical role in promoting breast cancer aggressiveness, particularly in the triple-negative subtype.
  • mtSrc promotes aggressiveness through phosphorylation of the mitochondrial single-stranded DNA-binding protein, leading to reduced mtDNA levels and mitochondrial dysfunction.
  • The subcellular localization of Src kinase, specifically within mitochondria, is a crucial factor in breast cancer progression and warrants consideration for therapeutic development.

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