Lapatinib induces IL-6 expression via MAPK pathway in triple-negative breast cancer cells

Lapatinib induces IL-6 expression via MAPK pathway in triple-negative breast cancer cells

Yu-Chun Hsiao

, Mong-Liang Chen

, Yun-Ju Chen

, Chih-Hsin Tang

and Wei-Chien Huang

1

_{Graduate Institute of Cancer Biology and Drug Discovery, China Medical University, Taichung 404, Taiwan ;}

_{Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan;}

3

_{Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan ;}

4

_{Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan ;}

_{Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan;}

6

_{Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan;}

_{Department of Biotechnology, Asia University, Taichung 413, Taiwan}

Abstract

Lapatinib, the dual Epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), have been tested in triple negative breast cancer (TNBC) patients in several clinical studies. However, limited clinic benefit was observed, and unexpectedly the metastatic ability of TNBC cells was even enhanced by these anti-cancer drugs in our previous studies. In this study, we found that induction of interleukin-6 (IL-6) expression was induced in lapatinib-treated cells to contribute to their increased ability of migration. Treatment of cells with the IL-6 antibody abolished the lapatinib-induced cell migration. In response to lapatinib treatment, Raf-1, Mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinases (JNK), p38 mitogen activated protein kinase (p38 or p38-MAPK), and activator protein 1 (AP-1) signaling pathways were activated to mediate the induction of IL-6 level. Furthermore, downregulation of miR-7 was found to result in the lapatinib-induced activation of Raf-1signaling pathway and IL-6 expression. Taken together, our results indicated that lapatinib enhanced the migratory ability of TNBC through induction of IL-6 expression via the Raf-1, MAPK, JNK, p38, and AP-1 pathways by downregulating microRNA-7 expression.

Figure 1. Treatment with lapatinib up-regulated IL-6 expression in both HER2-positive and -negative breast cancer cells.

Figure 2. Up-regulation of IL-6 mediate lapatinib-induced migrationn.

Figure 4. Lapatinib treatment induced c-Jun activation through Raf-1/MAPK signaling pathway.

Figure 6. Overexpression of miR-7 down-regulated Raf-1/ERK1/2 signaling and reduced IL-6 expression in MDA-MB-231/Lap cells.

Figure 5. Raf-1/MAPK-activated AP-1 was involved in lapatinib-induced IL-6 expression.

Acknowledgement

This work was supported by grants from E-Da Hospital (EDAHT100024, EDAHT100026), the National Science Council of Taiwan (NSC 102-2320-B-039-054-MY3 and NSC 102-2320-B-039-052 to W.C.H), China Medical

University (CMU100-NSC-09), and the National Health Research Institutes of Taiwan (NHRI-EX103-10329BI to W.C.H).

Figure 3. Lapatinib induced IL-6 expression through Raf-1 and MAP Kinase signaling pathway.