Lapatinib–induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors

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• 作者：Yun-Ju Chen (1) (2)
  Ming-Hsin Yeh (3)
  Meng-Chieh Yu (4) (7)
  Ya-Ling Wei (4)
  Wen-Shu Chen (12) (4)
  Jhen-Yu Chen (7) (8)
  Chih-Yu Shih (7)
  Chih-Yen Tu (13) (5) (6)
  Chia-Hung Chen (10) (5) (9)
  Te-Chun Hsia (6) (9)
  Pei-Hsuan Chien (1)
  Shu-Hui Liu (11) (14)
  Yung-Luen Yu (15) (4) (7) (8)
  Wei-Chien Huang (15) (4) (7) (8)
  
• 刊名：Breast Cancer Research
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：15
• 期：6
• 全文大小：
• 作者单位：Yun-Ju Chen (1) (2)
  Ming-Hsin Yeh (3)
  Meng-Chieh Yu (4) (7)
  Ya-Ling Wei (4)
  Wen-Shu Chen (12) (4)
  Jhen-Yu Chen (7) (8)
  Chih-Yu Shih (7)
  Chih-Yen Tu (13) (5) (6)
  Chia-Hung Chen (10) (5) (9)
  Te-Chun Hsia (6) (9)
  Pei-Hsuan Chien (1)
  Shu-Hui Liu (11) (14)
  Yung-Luen Yu (15) (4) (7) (8)
  Wei-Chien Huang (15) (4) (7) (8)
  
  1. Department of Medical Research, E-Da Hospital, Kaohsiung, 824, Taiwan
  2. Department of Biological Science & Technology, I-Shou University, Kaohsiung, 824, Taiwan
  3. Section of Breast Surgery, China Medical University and Hospital, Taichung, 404, Taiwan
  4. Center for Molecular Medicine, China Medical University and Hospital, Taichung, 404, Taiwan
  7. Graduate Institute of Cancer Biology, China Medical University, Taichung, 404, Taiwan
  12. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
  8. Cancer Biology and Drug Discovery, China Medical University, Taichung, 404, Taiwan
  13. Department of Life Science, National Chung-Hsing University, Taichung, 402, Taiwan
  5. Division of Pulmonary and Critical Care Medicine, China Medical University and Hospital, Taichung, 404, Taiwan
  6. Department of Internal Medicine, China Medical University and Hospital, Taichung, 404, Taiwan
  10. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 404, Taiwan
  9. Department of Respiratory Therapy, China Medical University, Taichung, 404, Taiwan
  11. Department of Public Health, China Medical University, Taichung, 404, Taiwan
  14. Department of Health Care and Social Work, Yu Da University of Science and Technology, Miaoli, Taiwan
  15. Department of Biotechnology, Asia University, Taichung, 413, Taiwan
  
• ISSN：1465-5411

文摘

Introduction Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Methods Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. Results Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. Conclusions These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.