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Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation

Jennifer F Raven1, Virginie Williams, Shuo Wang

  • 1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.

Cell Cycle (Georgetown, Tex.)
|February 12, 2011
PubMed

Insights

Signal transducer and activator of transcription 1 (Stat1) suppresses breast cancer development, independent of its phosphorylation sites. This uncharacterized anti-tumor activity has implications for treating ErbB2-positive breast cancers.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 1 (Stat1) is a known regulator of innate immunity and tumor immune surveillance.
  • The specific role of Stat1 within the tumor microenvironment, particularly in breast cancer signaling, remains incompletely understood.
  • Stat1 phosphorylation at tyrosine 701 (Y701) and serine 727 (S727) is crucial for interferon (IFN) signaling.

Purpose of the Study:

  • To investigate the role of Stat1 phosphorylation in breast cancer cells, specifically in relation to ErbB2/HER-2 signaling.
  • To elucidate the tumor-site specific functions of Stat1 in ErbB2/HER-2-mediated breast oncogenesis.
  • To explore the potential of Stat1 as a therapeutic target in ErbB2-positive breast cancers.

Main Methods:

  • Analysis of Stat1 Y701 phosphorylation in human breast tumor cells and ErbB2/HER-2-transfected cells.
  • Pharmacological inhibition of ErbB2/HER-2 to assess its effect on Stat1 phosphorylation.
  • Xenograft tumor assays in mouse embryonic fibroblasts to evaluate Stat1's anti-tumor function.
  • Studies in transgenic mice to examine Stat1's role in Neu-mediated breast tumorigenesis.

Main Results:

  • Stat1 Y701 phosphorylation was elevated in human breast tumor cells with high ErbB2/HER-2 levels and in cells expressing ErbB2/Neu.
  • Inhibition of ErbB2/HER-2 reduced Stat1 Y701 phosphorylation, suggesting an atypical role in suppressing ErbB2/HER-2 signaling.
  • Stat1 suppressed tumor development mediated by activated ErbB2/Neu, independent of Y701 and S727 phosphorylation.
  • Stat1 demonstrated immune regulatory and tumor-site specific mechanisms to suppress Neu-mediated breast tumorigenesis.

Conclusions:

  • Stat1 exhibits a previously unrecognized anti-tumor activity in ErbB2/Neu-mediated cell transformation and breast oncogenesis.
  • This anti-tumor function of Stat1 is independent of its Y701 and S727 phosphorylation.
  • The findings suggest potential implications for the diagnosis and treatment of ErbB2-positive breast cancers.

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