Lapatinib-Mediated Cyclooxygenase-2 Expression via Epidermal Growth Factor Receptor/HuR Interaction Enhances the Aggressiveness of Triple-Negative Breast Cancer Cells

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.

Concurrent Expression of Cyclo-oxygenase-2 and Epidermal Growth Factor Receptor in Canine Malignant Mammary Tumours

“…Furthermore, recent work performed with human breast cancer cell lines suggested that LapatinibÔ (LC Laboratories, Woburn, Massachusetts, USA), a dual EGFR/HER2 kinase inhibitor, may increase the migration and invasion of cells by up-regulating There is a significant association between COX-2 and EGFR expression (P ¼ 0.001). EGFR and COX-2 (Hsia et al, 2013). These findings and the evidence that 25.5% of tumours in the present study showed high expression of COX-2 and EGFR, emphasizes the need for additional studies with selective inhibitors of the two molecules in order to verify their true clinical effectiveness in CMTs.…”

“…In human cancer, several studies have focused on these molecules, mainly in lung and oesophageal adenocarcinomas, non-small cell lung cancer and nasopharyngeal, colonic, colorectal and cholangiocarcinomas (Pai et al, 2003;Ceccarelli et al, 2005;Han and Wu, 2005;Li et al, 2006;Van Dyke et al, 2008;Huang et al, 2010;Li et al, 2011). In contrast, there are fewer studies of these molecules in human breast cancer (Lanza-Jacoby et al, 2006;Hsia et al, 2013). In the dog, to the best of our knowledge, no studies have investigated the association between COX-2 and EGFR expression in mammary tumours.…”

Lapatinib–induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors

“…Lapatinib has recently been found to up-regulate the gene expression of proapoptotic TRAIL death receptors DR4 and DR5 [21]. Our recent study also showed that lapatinib can induce the NF-κB-targeted gene COX-2 in a HER2/EGFR-independent manner [22]. These observations raise the possibility that lapatinib may increase NF-κB activity independently of targeting EGFR and HER2.…”

Post-Transcriptional Controls by Ribonucleoprotein Complexes in the Acquisition of Drug Resistance

“…Hsia et al presented lapatinib-mediated upregulation of aggressiveness in breast cancer cells [26]. Lapatinib, a dual epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) kinase inhibitor, is used for the treatment of advanced HER2-positive breast cancer [27].…”