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

ABSTRACT: 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.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.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.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.

SUBMITTER: Aceto N

PROVIDER: S-EPMC4053109 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Aceto Nicola N Duss Stephan S MacDonald Gwen G Meyer Dominique S DS Roloff Tim-C TC Hynes Nancy E NE Bentires-Alj Mohamed M

Breast cancer research : BCR 20121012 5

<h4>Introduction</h4>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 ...[more]

PMID: 23062209

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Project description:IntroductionThe human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2-addicted tumors. Although lapatinib, an FDA-approved small-molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER-directed therapies is of critical importance.MethodsUsing a functional protein-pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib-sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and similar TKIs.ResultsThe signaling analysis revealed that whereas HER2 was appropriately inhibited in lapatinib-resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR-persistent activation, we found that lapatinib-resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling, as seen in the parental lapatinib-sensitive cell lines, but instead were dependent on a heregulin (HRG)-driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3-mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings.ConclusionsMolecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic.

Dataset Information

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

Publications

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

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