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HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation

David B Vaught1, Jamie C Stanford, Christian Young

  • 1Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.

Cancer Research
|March 31, 2012
PubMed

Insights

The human epidermal growth factor receptor 3 (HER3/ErbB3) is crucial in preventing early breast cancer development in HER2-amplified models. Inhibiting HER3/ErbB3 may offer new therapeutic strategies for HER2-positive breast tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • HER2-amplified breast cancers often develop resistance to HER2 inhibitors, with HER3/ErbB3 implicated in this process.
  • The role of HER3/ErbB3 in the initial stages of breast epithelial transformation is not well understood.

Purpose of the Study:

  • To investigate the role of HER3/ErbB3 in the early development and progression of HER2-amplified breast cancer.
  • To determine if targeting HER3/ErbB3 can impact tumor formation and response to HER2-targeted therapy.

Main Methods:

  • Utilized mouse mammary-specific models with Cre-mediated ErbB3 ablation in conjunction with HER2 overexpression (MMTV-HER2, MMTV-Neu).
  • Employed a transgenic model expressing HER2 and Cre from a single polycistronic transcript to assess tumor penetrance.
  • Analyzed proliferation, apoptosis, signaling pathways (Akt, p44/42), tumor growth, and response to lapatinib upon ErbB3 manipulation.

Main Results:

  • ErbB3 ablation prevented the progressive transformation of HER2-overexpressing mammary epithelium, reducing proliferation and increasing apoptosis.
  • Loss of ErbB3 significantly decreased palpable tumor penetrance (93.3% to 6.7%) and ductal carcinoma in situ formation.
  • ErbB3 deficiency impaired Akt and p44/42 phosphorylation, reduced tumor growth, and enhanced sensitivity to lapatinib, with partial rescue by a phosphatidylinositol 3-kinase-binding deficient mutant.

Conclusions:

  • HER3/ErbB3 plays a critical role in promoting HER2-induced breast epithelial changes throughout tumor initiation, progression, and post-formation.
  • Targeting HER3/ErbB3 is a promising strategy for preventing and treating HER2-amplified breast tumors, potentially overcoming therapeutic resistance.

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