TY - JOUR T1 - Lapatinib-mediated COX-2 Expression Via EGFR/HuR Interaction Enhances the Aggressiveness of Triple-negative Breast Cancer Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.082743 SP - mol.112.082743 AU - Te-Chun Hsia AU - Chih-Yen Tu AU - Yun-Ju Chen AU - Ya-Ling Wei AU - Mien-Chieh Yu AU - Sheng-Chie Hsu AU - Shing-Ling Tsai AU - Wen-Shu Chen AU - Ming-Hsin Yeh AU - Chia-Jui Yen AU - Yung-Luen Yu AU - Tzung-Chi Huang AU - Chih-Yang Huang AU - Mien-Chie Hung AU - Wei-Chien Huang Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/01/25/mol.112.082743.abstract N2 - Lapatinib, a dual EGFR/HER2 kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the anti-tumor 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. ER -