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Dimerization of EGFR and HER2 induces breast cancer cell motility through STAT1-dependent ACTA2 induction

Myeongjin Jeon1,2, Daeun You1,2, Soo Youn Bae1

  • 1Department of Surgery, Samsung Medical Center, Gangnam-gu, Seoul 06351, Korea.

Oncotarget
|September 9, 2017
PubMed

Insights

EGFR and HER2 dimerization promotes breast cancer invasion and metastasis. This process involves increased alpha-smooth muscle actin (ACTA2) expression via the JAK2/STAT1 pathway, leading to poor patient survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Epidermal Growth Factor Receptor (EGFR) and Human Epidermal growth factor Receptor 2 (HER2) dimerization is linked to poor breast cancer prognosis, including tumor growth and invasion.
  • The precise molecular mechanisms driving these outcomes post-dimerization in breast cancer remain incompletely understood.

Purpose of the Study:

  • To elucidate the signaling pathways and molecular events following EGFR and HER2 dimerization in breast cancer.
  • To investigate the role of alpha-smooth muscle actin (ACTA2) and signal transducer and activator of transcription 1 (STAT1) in HER2-driven breast cancer progression.

Main Methods:

  • Overexpression and knockdown (siRNA, shRNA) of HER2, ACTA2, and STAT1 in EGFR-positive breast cancer cell lines (MDA-MB231 HER2, 4T1).
  • Inhibition of STAT1 and JAK2 signaling pathways using fludarabine and AG490, respectively.
  • Analysis of ACTA2 and STAT1 expression in patient tumor samples and correlation with relapse-free survival.
  • Assessment of cell motility and lung metastasis in mouse models.

Main Results:

  • HER2 overexpression significantly increased ACTA2 and STAT1 expression in breast cancer cells, while HER2 knockdown decreased ACTA2.
  • ACTA2 expression was dependent on JAK2/STAT1 signaling, as indicated by inhibition with fludarabine and AG490, and enhancement with STAT1 overexpression.
  • Elevated ACTA2, STAT1, and HER2 levels correlated with decreased relapse-free survival in high-risk breast cancer patients.
  • ACTA2 knockdown suppressed cancer cell motility and reduced lung metastasis in vivo.

Conclusions:

  • EGFR and HER2 dimerization induces ACTA2 expression through the JAK2/STAT1 signaling pathway.
  • Aberrant ACTA2 expression driven by HER2 signaling accelerates breast cancer cell invasiveness and metastasis.
  • Targeting the JAK2/STAT1/ACTA2 axis may offer therapeutic strategies for HER2-positive breast cancer.
Keywords:
ACTA2HER2STAT1invasionmetastasis

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