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A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer

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Abstract

Endometrial cancers have been recently molecularly characterized; amplifications of human epidermal growth factor receptor 2 (HER2) were seen in 25 % of the serous-like tumors, and mutations in the PI(3)K/AKT pathways were seen in 93 % of endometrioid tumors. These new findings about endometrial cancer suggest a potential for targeted therapy with lapatinib, a dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases. However, the clinical efficacy of lapatinib in phase II clinical trials for the treatment of endometrial cancers was only minimal. In this study, we investigated the signaling changes induced by lapatinib in endometrial cancer, which may improve its therapeutic efficacy in molecularly selected patient groups. We identified one of the final molecular targets of lapatinib to be interstitial collagenase, matrix metallopeptidase 1 (MMP1). Lapatinib suppresses MMP1 through EGFR and HER2, and their downstream ERK and AKT signaling pathways. We also found that the activating protein-1 binding site of MMP1 promoter is required for its transcriptional activation, which may be unique for endometrial cancers. Our results also showed that forced expression of active ERK or active AKT mutants rescued MMP1 expression from lapatinib suppression, further suggesting the importance of molecular selection to find appropriate patients with endometrial cancer for future clinical trials with any targeted therapies.

Key message

  • MMP1 expression was high in tissues and sera in patients with endometrial cancer.

  • Lapatinib inhibited MMP1 via both HER2 and EGFR signaling pathways.

  • Both AKT and ERK need to be inhibited for efficient MMP1 suppression by lapatinib.

  • Activating protein-1 (AP-1) binding site of MMP1 promoter is uniquely required for MMP1 activation in endometrial cancer.

  • Suppression of both c-fos and c-Jun bound to AP1 binding site is required for lapatinib inhibition.

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Acknowledgments

This study was supported by grants from the Department of Health, Taiwan (DOH101-TD-B-111-005), and Chang Gung Medical Research Foundation (CMRPG391441-4, CMRPG3C0281). The authors are grateful for the English editing by Dr. Shihyee Mimi Wang (Department of Obstetrics and Gynecology, White Memorial Medical Center, Los Angeles, CA).

Conflict of interest

The authors declared no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan

    Chiao-Yun Lin, Angel Chao, Tzu-Hao Wang, An-Shine Chao, Huei-Jean Huang, Hung-Hsueh Chou, Ting-Chang Chang & Chyong-Huey Lai

  2. Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chiao-Yun Lin, Angel Chao, Tzu-Hao Wang, Swei Hsueh, Huei-Jean Huang, Hung-Hsueh Chou, Ting-Chang Chang & Chyong-Huey Lai

  3. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Tzu-Hao Wang & Yun-Shien Lee

  4. School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Tzu-Hao Wang

  5. Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan

    Swei Hsueh

  6. Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan

    Yun-Shien Lee

  7. Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei, Taiwan

    Tzu-I Wu

  8. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center, 5 Fushin St., Guishan, Taoyuan 333, Taiwan

    Chyong-Huey Lai

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  1. Chiao-Yun Lin
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Correspondence to Chyong-Huey Lai.

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Chiao-Yun Lin, Angel Chao, and Tzu-Hao Wang contribute equally to this work.

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Lin, CY., Chao, A., Wang, TH. et al. A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer. J Mol Med 92, 969–981 (2014). https://doi.org/10.1007/s00109-014-1163-0

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  • DOI: https://doi.org/10.1007/s00109-014-1163-0

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