Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion.

Abstract

INTRODUCTION:

The tyrosine kinase receptors HER2 and HER3 play an important role in breast cancer. The HER2/HER3 heterodimer is a critical oncogenic unit associated with reduced relapse-free and decreased overall survival. While signaling cascades downstream of HER2 and HER3 have been studied extensively at the level of post-translational modification, little is known about the effects of HER2/HER3 overexpression and activation on gene expression in breast cancer. We have now defined the genetic landscape induced by activation of the HER2/HER3 unit in mammary cells, and have identified interleukin (IL)8 and CXCR1 as potential therapeutic targets for the treatment of HER2/HER3-overexpressing breast cancers.

METHODS:

Three-dimensional (3D) cultures, invasion and migration assays were used to determine the effects of HER2 and HER3 co-expression and activation. Gene expression analysis was performed to identify the gene network induced by HER2/HER3 in 3D cultures. Bioinformatic analysis and neutralizing antibodies were used to identify key mediators of HER2/HER3-evoked invasion.

RESULTS:

Co-expression of the tyrosine kinase receptors HER2 and HER3 induced migration and invasion of MCF10A cells. Microarray analysis of these cells revealed a specific "HER2/HER3 signature" comprising 80 upregulated transcripts, with IL8 being the highest (11-fold upregulation). Notably, examination of public datasets revealed high levels of IL8 transcripts in HER2-enriched as well as basal-like primary breast tumors, two subtypes characterized by a particularly poor prognosis. Moreover, IL8 expression correlated with high tumor grade and ER-negative status. Importantly, treatment with IL8-neutralizing antibodies prevented invasion of MCF10A-HER2/HER3 and BT474 cells in 3D cultures, highlighting the importance of IL8 autocrine signaling upon HER2/HER3 activation.

CONCLUSIONS:

Our findings demonstrate that HER2 and HER3 co-expression induces IL8 autocrine signaling, leading to the invasion of mammary cells. Agents targeting IL8 or its receptor CXCR1 may be useful for the treatment of HER2/HER3/IL8-positive breast cancers with invasive traits.

• Authors: Nicola Aceto, Stephan Duss, Gwen MacDonald, Dominique S Meyer, Tim-C Roloff, Nancy E Hynes, Mohamed Bentires-Alj
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 14 Issue 5 Pg. R131 (Oct 12 2012) ISSN: 1465-542X [Electronic] England
• PMID: 23062209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• Neuregulin-1
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Autocrine Communication
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Datasets as Topic
• Female
• Gene Expression
• Gene Expression Profiling
• Humans
• Interleukin-8 (metabolism)
• Models, Biological
• Neoplasm Grading
• Neuregulin-1 (pharmacology)
• Receptor, ErbB-2 (genetics)
• Receptor, ErbB-3 (genetics)
• Signal Transduction
• Spheroids, Cellular
• Tumor Cells, Cultured