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Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer

Jamie K Miller1, David L Shattuck, Ellen Q Ingalla

  • 1School of Medicine, Davis Cancer Center, University of California at Davis, Sacramento, California 95817, USA.

Cancer Research
|October 17, 2008
PubMed

Insights

Loss of LRIG1, an ErbB2 regulator, is common in ErbB2-positive breast tumors. Suppressed LRIG1 levels promote tumor growth and ErbB2 overexpression, suggesting a feedback loop in breast cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • ErbB2 receptor tyrosine kinase overexpression is prevalent in breast cancer, correlating with poor prognosis and treatment resistance.
  • LRIG1 is a recently identified negative regulator of ErbB receptors, including ErbB2.

Purpose of the Study:

  • To investigate the role of LRIG1 in ErbB2-positive (ErbB2(+)) breast cancer.
  • To determine if LRIG1 suppression contributes to ErbB2(+) breast tumor initiation and growth.

Main Methods:

  • Analysis of LRIG1 protein levels in ErbB2-induced mouse mammary tumors and human ErbB2(+) breast tumors.
  • RNA interference (RNAi)-mediated knockdown of LRIG1 in ErbB2-overexpressing breast cancer cell lines (MDA-MB-453, BT474).
  • Ectopic expression of LRIG1 in breast cancer cells.

Main Results:

  • LRIG1 protein levels were significantly suppressed in both mouse and human ErbB2(+) breast tumors.
  • LRIG1 knockdown in ErbB2-overexpressing cells increased ErbB2 levels and augmented cellular proliferation.
  • Ectopic LRIG1 expression reversed these effects.
  • ErbB receptor activation suppressed LRIG1 protein levels in breast tumor cells but not in normal breast epithelial cells.

Conclusions:

  • Suppression of LRIG1 protein is a common characteristic of breast tumors.
  • A feed-forward regulatory loop exists in breast tumor cells where ErbB2 signaling suppresses LRIG1, leading to further ErbB2 overexpression and promoting tumor growth.

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