RT Journal Article SR Electronic T1 Lapatinib-Mediated Cyclooxygenase-2 Expression via Epidermal Growth Factor Receptor/HuR Interaction Enhances the Aggressiveness of Triple-Negative Breast Cancer Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 857 OP 869 DO 10.1124/mol.112.082743 VO 83 IS 4 A1 Te-Chun Hsia A1 Chih-Yen Tu A1 Yun-Ju Chen A1 Ya-Ling Wei A1 Meng-Chieh Yu A1 Sheng-Chie Hsu A1 Shing-Ling Tsai A1 Wen-Shu Chen A1 Ming-Hsin Yeh A1 Chia-Jui Yen A1 Yung-Luen Yu A1 Tzung-Chi Huang A1 Chih-Yang Huang A1 Mien-Chie Hung A1 Wei-Chien Huang YR 2013 UL http://molpharm.aspetjournals.org/content/83/4/857.abstract AB 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.