Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells

Te Chun Hsia, Chih Yen Tu, Yun Ju Chen, Ya Ling Wei, Meng Chieh Yu, Sheng Chie Hsu, Shing Ling Tsai, Wen Shu Chen, Ming Hsin Yeh, Chia Jui Yen, Yung Luen Yu, Tzung Chi Huang, Chih Yang Huang, Mien Chie Hung, Wei Chien Huang

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.

Original languageEnglish
Pages (from-to)857-869
Number of pages13
JournalMolecular Pharmacology
Volume83
Issue number4
DOIs
Publication statusPublished - 2013 Apr

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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