Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6.

Abstract

Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.

• Authors: Yu-Chun Hsiao, Ming-Hsin Yeh, Yun-Ju Chen, Ju-Fang Liu, Chih-Hsin Tang, Wei-Chien Huang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37965-78 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26513016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• IL6 protein, human
• Interleukin-6
• MIRN7 microRNA, human
• MicroRNAs
• Quinazolines
• RNA, Messenger
• Lapatinib
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinase 1

Topics

• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Interleukin-6 (genetics, metabolism)
• Lapatinib
• MicroRNAs (genetics)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-raf (genetics, metabolism)
• Quinazolines (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tumor Cells, Cultured