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The ShcA PTB domain functions as a biological sensor of phosphotyrosine signaling during breast cancer progression

Ryuhjin Ahn1, Valerie Sabourin, Jacqueline R Ha

  • 1Lady Davis Institute for Medical Research, McGill Centre for Bioinformatics, McGill University, Goodman Cancer Research Centre, Montreal, Quebec, Canada.

Cancer Research
|May 23, 2013
PubMed

Insights

The ShcA (SHC1) protein’s PTB domain plays a complex role in breast cancer. Disrupting its phosphotyrosine binding delays tumor onset but paradoxically increases tumor growth and angiogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • ShcA (SHC1) is an adapter protein with SH2 and PTB domains crucial for receptor tyrosine kinase (RTK) signaling.
  • The precise role of the ShcA PTB domain in tumorigenesis remains incompletely understood.

Purpose of the Study:

  • To investigate the in vivo role of the ShcA PTB domain in breast cancer development and progression.
  • To elucidate the downstream signaling pathways affected by PTB domain dysfunction.

Main Methods:

  • Utilized a transgenic mouse model (MMTV-PyMT) expressing a phosphotyrosine-binding deficient ShcA mutant (Shc R175Q).
  • Analyzed tumor onset, growth, and angiogenesis.
  • Assessed fibronectin and integrin α5/β1 expression and activation of downstream signaling pathways including Src and proangiogenic RTKs.
  • Defined a ShcR175Q-dependent gene signature.

Main Results:

  • Transgenic expression of Shc R175Q delayed mammary tumor onset but significantly increased tumor growth and angiogenesis.
  • Shc R175Q-expressing tumors showed increased fibronectin secretion and integrin α5/β1 signaling, activating Src.
  • Activated Src led to phosphorylation of proangiogenic RTKs (PDGFR, FGFR, Met), increasing VEGF secretion.
  • A ShcR175Q-dependent gene signature correlated with high microvessel density in breast cancer patients.

Conclusions:

  • The ShcA PTB domain plays a dual role in breast cancer, influencing both tumor initiation and progression.
  • Intracellular signaling pathways downstream of the ShcA PTB domain are critical regulators of tumor angiogenesis and growth.
  • Findings provide in vivo evidence for the ShcA PTB domain's complex contribution to tumorigenesis and identify a potential biomarker for stratifying patients.

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