In breast cancer, the HER2/neu oncoprotein, which belongs to the epidermal growth factor receptor family, with tyrosine kinase activity, may trigger activation of the phosphoinositide-3 kinase (PI3K)/Akt pathway, which controls cell proliferation, survival, migration, and invasion. In this study, we examined the question of whether or not ANT2 (adenine nucleotide translocase 2) shRNA-mediated down-regulation of HER2/neu and inhibitory effects on the PI3K/Akt signaling pathway suppressed migration and invasiveness of breast cancer cells.

We utilized an ANT2 vector-based RNA interference approach to inhibition of ANT2 expression, and the HER2/neu-overexpressing human breast cancer cell line, SK-BR3, was used throughout the study.

In this study, ANT2 shRNA decreased HER2/neu protein levels by promoting degradation of HER2/neu protein through dissociation from HSP90 (heat shock protein 90). As a result, ANT2 shRNA induced inhibitory effects on the PI3K/Akt signaling pathway. Inhibition of PI3K/Akt signaling by ANT2 shRNA caused down-regulation of MT1-MMP (membrane-type 1 matrix metalloproteinase) and VEGF expression, decreased MMP2 (matrix metalloproteinase 2) and MMP9 activity, and suppressed migration and invasion of breast cancer cells.

These results indicate that knock-down of ANT2 shRNA down-regulates HER2/neu through suppression of HSP90's function and inhibits the PI3K/Akt signaling pathway, resulting ultimately in suppressed migration and invasion of breast cancer cells.

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