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The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

Víctor Mayoral-Varo1, María Pilar Sánchez-Bailón1,2, Annarica Calcabrini1,3

  • 1Instituto de Investigaciones Biomédicas A, Sols/Dpto. Bioquímica (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain.

Cancers
|February 3, 2021
PubMed

Insights

The SH2 domain of c-Src kinase is crucial for triple-negative breast cancer (TNBC) stem cell self-renewal and tumor progression. Targeting this domain offers a potential new therapeutic strategy for TNBC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Src family kinases (SFKs) are implicated in human cancers, primarily through their tyrosine kinase activity.
  • The roles of SFK adapter domains (SH2 and SH3) in tumorigenesis, particularly in triple-negative breast cancer (TNBC), are less understood.
  • The c-Src SH2 domain's specific involvement in TNBC progression requires further investigation.

Purpose of the Study:

  • To investigate the role of the c-Src SH2 adapter domain in triple-negative breast cancer (TNBC) pathogenesis.
  • To evaluate the impact of inhibiting the c-Src SH2 domain on TNBC cell behavior and tumorigenic potential.
  • To explore the c-Src SH2 domain as a potential therapeutic target for TNBC.

Main Methods:

  • Utilized SUM159PT and MDA-MB-231 TNBC cell lines with a tetracycline-inducible system to express a c-Src variant with a mutated SH2 domain (R175L).
  • Assessed the effects of SH2 domain mutation on breast cancer stem cell (BCSC) self-renewal, anchorage-independent growth, proliferation, migration, and invasiveness.
  • Transfected cells with aptamers targeting the SH2 domain of c-Src to evaluate its functional role in TNBC progression.

Main Results:

  • Expression of the c-Src SH2 domain mutant (R175L) significantly reduced BCSCs' self-renewal capability.
  • The c-Src SH2 domain was found to play a critical role in regulating anchorage-independent growth, proliferation, migration, and invasiveness of TNBC cells.
  • Aptamers targeting the SH2-c-Src domain inhibited proliferation, migration, and invasiveness in TNBC cell lines, confirming the domain's involvement in tumorigenesis.

Conclusions:

  • The SH2 adapter domain of c-Src is essential for mammary gland carcinogenesis and TNBC progression.
  • Inhibiting the c-Src SH2 domain demonstrates significant anti-tumor effects in vitro.
  • The c-Src SH2 domain represents a promising therapeutic target, suggesting combined treatments with kinase inhibitors could improve outcomes for TNBC patients.
Keywords:
SH2 domainaptamersc-Srcinactivating point mutationtriple-negative breast cancer (TNBC)

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