Modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer

Xiao Feng Le, Maria I. Almeida, Weiqun Mao, Riccardo Spizzo, Simona Rossi, Milena S. Nicoloso, Shu Zhang, Yun Wu, George A. Calin, Robert C. Bast

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere41170
JournalPLoS One
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 19 2012

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MicroRNAs
microRNA
cell movement
breast neoplasms
Cell Movement
Modulation
Breast Neoplasms
Cells
mouse MIRN194 microRNA
Trastuzumab
apoptosis
Up-Regulation
Cell Migration Inhibition
cytoskeletal proteins
Apoptosis
Antibodies, Monoclonal, Humanized
Cytoskeletal Proteins
3' untranslated regions
luciferase
Oncogene Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Le, X. F., Almeida, M. I., Mao, W., Spizzo, R., Rossi, S., Nicoloso, M. S., ... Bast, R. C. (2012). Modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer. PLoS One, 7(7), [e41170]. https://doi.org/10.1371/journal.pone.0041170

Modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer. / Le, Xiao Feng; Almeida, Maria I.; Mao, Weiqun; Spizzo, Riccardo; Rossi, Simona; Nicoloso, Milena S.; Zhang, Shu; Wu, Yun; Calin, George A.; Bast, Robert C.

In: PLoS One, Vol. 7, No. 7, e41170, 19.07.2012.

Research output: Contribution to journalArticle

Le, XF, Almeida, MI, Mao, W, Spizzo, R, Rossi, S, Nicoloso, MS, Zhang, S, Wu, Y, Calin, GA & Bast, RC 2012, 'Modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer', PLoS One, vol. 7, no. 7, e41170. https://doi.org/10.1371/journal.pone.0041170
Le, Xiao Feng ; Almeida, Maria I. ; Mao, Weiqun ; Spizzo, Riccardo ; Rossi, Simona ; Nicoloso, Milena S. ; Zhang, Shu ; Wu, Yun ; Calin, George A. ; Bast, Robert C. / Modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer. In: PLoS One. 2012 ; Vol. 7, No. 7.
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