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

Chiao Yun Lin, Angel Chao, Tzu Hao Wang, Swei Hsueh, Yun Shien Lee, Tzu I. Wu, An Shine Chao, Huei Jean Huang, Hung Hsueh Chou, Ting Chang Chang, Chyong Huey Lai

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)969-981
Number of pages13
JournalJournal of Molecular Medicine
Volume92
Issue number9
DOIs
Publication statusPublished - 2014

Fingerprint

Endometrial Neoplasms
Protein-Tyrosine Kinases
Binding Sites
Protein Binding
metallopeptidase-1
lapatinib
Phase II Clinical Trials
Matrix Metalloproteinase 1
Therapeutics
Epidermal Growth Factor Receptor
Transcriptional Activation
Neoplasms
Clinical Trials
Mutation
human ERBB2 protein
Serum

Keywords

  • EGFR
  • Endometrial cancer
  • HER2
  • Lapatinib
  • MMP1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)
  • Medicine(all)

Cite this

A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer. / Lin, Chiao Yun; Chao, Angel; Wang, Tzu Hao; Hsueh, Swei; Lee, Yun Shien; Wu, Tzu I.; Chao, An Shine; Huang, Huei Jean; Chou, Hung Hsueh; Chang, Ting Chang; Lai, Chyong Huey.

In: Journal of Molecular Medicine, Vol. 92, No. 9, 2014, p. 969-981.

Research output: Contribution to journalArticle

Lin, CY, Chao, A, Wang, TH, Hsueh, S, Lee, YS, Wu, TI, Chao, AS, Huang, HJ, Chou, HH, Chang, TC & Lai, CH 2014, 'A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer', Journal of Molecular Medicine, vol. 92, no. 9, pp. 969-981. https://doi.org/10.1007/s00109-014-1163-0
Lin, Chiao Yun ; Chao, Angel ; Wang, Tzu Hao ; Hsueh, Swei ; Lee, Yun Shien ; Wu, Tzu I. ; Chao, An Shine ; Huang, Huei Jean ; Chou, Hung Hsueh ; Chang, Ting Chang ; Lai, Chyong Huey. / A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer. In: Journal of Molecular Medicine. 2014 ; Vol. 92, No. 9. pp. 969-981.
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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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AU - Lee, Yun Shien

AU - Wu, Tzu I.

AU - Chao, An Shine

AU - Huang, Huei Jean

AU - Chou, Hung Hsueh

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