Breast cancer is the main cancer in female in the both developed and developing countries. It is also the leading cause of cancer mortality in most countries. Since about 20-30 percent of breast cancers have HER2 overexpression, anti-HER2 target therapies, such as trastuzumab and lapatinib, are developed for HER2 positive breast cancers. Lapatinib is a dual EGFR/HER2 tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, acquired resistance to lapatinib occurs within 6-12 months and the underlying molecular mechanisms remain unclear. Although lapatinib can effectively eliminate HER2-positive cells, the minor subpopulation of HER2low/neg cells within the HER2-positive tumors may escape from lapatinib therapy and be the seeds of the recurrent and metastatic lapatinib-refractory tumors. To investigate whether lapatinib has any effect on HER2low/neg cells, we chronically treated HER2-negative MDA-MB-231 breast cancer cells with lapatinib and unexpectedly found that the lapatinib-selected MDA-MB-231 (231/Lap) clones have higher migration and invasion abilities without altering their proliferation rates. The increased migration was due to the cyclooxygenase-2 (COX-2) overexpression, which was mediated by lapatinib-induced EGFR expression independent of its tyrosine kinase activity, and was attenuated by COX-2 inhibitors. Furthermore, the increased EGFR expression in 231/Lap cells was associated with down-regulation of microRNA-7, which was known as an EGFR-3’UTR-targeting microRNA. Treatment of 231/Lap cells with both EGFR siRNA and miR-7 resulted in the decreases in EGFR and COX-2 expressions, cell migration, and invasion. Together, our results revealed that long-term treatment of HER2low/neg cells with lapatinib diminished miR-7 expression, leading to EGFR and COX-2 overexpressions and subsequent increased cell migration. Our findings suggest that co-treatment with COX-2 inhibitors may reduce the metastasis and recurrence of breast tumor in patients who received lapatinib therapy.
