Abstract
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3′-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.
Highlights
IntroductionTreatment with trastuzumab (HerceptinH), a humanized murine anti-HER2 monoclonal antibody [1], produced an objective response rate of 15% in extensively pretreated patients [2] and in 26% of previously untreated women with HER2-overexpressing metastatic breast cancer [3]
HER2 is amplified and overexpressed in 25–30% of human breast cancers
We have found that treatment with trastuzumab affected expression of several miRNAs. miR-194 was upregulated and downregulated talin2, inhibited cell migration and invasion, which may contribute to the anti-tumor activity of trastuzumab on HER2-overexpressing breast cancer cells
Summary
Treatment with trastuzumab (HerceptinH), a humanized murine anti-HER2 monoclonal antibody [1], produced an objective response rate of 15% in extensively pretreated patients [2] and in 26% of previously untreated women with HER2-overexpressing metastatic breast cancer [3]. Trastuzumab provided one of the first deliberately targeted therapies for a human cancer and has become the first-line treatment of choice for patients with primary or recurrent HER2-overexpressing breast cancer [8]. Trastuzumab-based combination treatment with chemotherapy are, effective in 60–70% of the HER2-overexpressing breast cancers [7,9] and trastuzumab resistance often develops during the course of treatment [9,10]. Others have provided evidence that trastuzumab can cleave the extracellular domains of HER2 receptors [28,29], mediate antibody-dependent cellular cytotoxicity [30,31,32], and can induce apoptosis [33,34,35]
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