Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells.
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.
Department of Internal Medicine, China Medical University and Hospital, Taichung, Taiwan.
Te-Chun
TC
Hsia
Chih-Yen
CY
Tu
Yun-Ju
YJ
Chen
Ya-Ling
YL
Wei
Meng-Chieh
MC
Yu
Sheng-Chie
SC
Hsu
Shing-Ling
SL
Tsai
Wen-Shu
WS
Chen
Ming-Hsin
MH
Yeh
Chia-Jui
CJ
Yen
Yung-Luen
YL
Yu
Tzung-Chi
TC
Huang
Chih-Yang
CY
Huang
Mien-Chie
MC
Hung
Wei-Chien
WC
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D009361:Neoplasm Invasiveness; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016511:Severe Combined Immunodeficiency / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human