Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis

Fang Nie, Jian Yang, Song Wen, Yan Li An, Jie Ding, Sheng Hong Ju, Zhen Zhao, Hua Jun Chen, Xin Gui Peng, Stephen T.C. Wong, Hong Zhao, Gao Jun Teng

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Background: Brain-metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear. Methods: The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells (231-BR cells). EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo. Results: EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay, a wound-healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay, an anchorage-independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway. Conclusions: The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012.

Original languageEnglish (US)
Pages (from-to)5198-5209
Number of pages12
JournalCancer
Volume118
Issue number21
DOIs
StatePublished - Nov 1 2012

Keywords

  • brain metastasis
  • breast cancer
  • cell migration
  • epidermal growth factor receptor
  • proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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