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CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway

Neslihan Cabioglu1, Justin Summy, Claudia Miller

  • 1Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer Research
|August 3, 2005
PubMed

Insights

Stromal cell-derived factor-1alpha (SDF-1alpha) activates HER2-neu in breast cancer cells via CXCR4. This pathway, involving Src kinase, promotes cancer cell migration and metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • CXCR4, a receptor for CXCL12/SDF-1alpha, is implicated in breast cancer metastasis.
  • G protein-coupled receptor activation can lead to ligand-independent transactivation of HER2-neu.
  • HER2-neu is a key tyrosine kinase receptor often overexpressed in breast cancer.

Purpose of the Study:

  • To investigate the mechanism of SDF-1alpha-induced HER2-neu activation in breast cancer cells.
  • To determine the role of CXCR4 and Src kinase in SDF-1alpha-mediated HER2-neu transactivation and cell migration.

Main Methods:

  • Utilized breast cancer cell lines (MDA-MB-361, SKBR3) expressing both CXCR4 and HER2-neu.
  • Employed inhibitors: AMD3100 (CXCR4 inhibitor), PKI 166 (EGFR/HER2-neu inhibitor), and PP2 (Src kinase inhibitor).
  • Assessed HER2-neu phosphorylation and SDF-1alpha-stimulated cell migration.

Main Results:

  • SDF-1alpha induced HER2-neu phosphorylation in MDA-MB-361 and SKBR3 cells.
  • AMD3100, PKI 166, and PP2 inhibited SDF-1alpha-induced HER2-neu phosphorylation.
  • Inhibition of Src kinase or EGFR/HER2-neu signaling reduced SDF-1alpha-stimulated cell migration.

Conclusions:

  • SDF-1alpha stimulation of CXCR4 leads to HER2-neu transactivation via Src kinase activation.
  • This novel pathway contributes to breast cancer cell migration.
  • Targeting the CXCR4-Src-HER2-neu axis may offer therapeutic strategies for breast cancer metastasis.

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