Interleukin-6 expression contributes to lapatinib resistance through maintenance of stemness property in HER2-positive breast cancer cells.
Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.
The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.|Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 413, Taiwan.
Wei-Chien
WC
Huang
School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan.|Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan.
Chao-Ming
CM
Hung
School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan.|Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan.
Ching-Ting
CT
Wei
Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan.
Tsung-Ming
TM
Chen
Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan.
Pei-Hsuan
PH
Chien
School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan.
Hsiao-Lin
HL
Pan
Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Yueh-Ming
YM
Lin
School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan.|Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan.|Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan.
Yun-Ju
YJ
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D015854:Up-Regulation
D000970:Antineoplastic Agents; D015850:Interleukin-6; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C508600:IL6 protein, human; C494086:STAT3 protein, human; C508053:ERBB2 protein, human
HER2; breast cancer; interleukin-6; lapatinib; resistance
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