Degradation of HER2/neu by ANT2 shRNA suppresses migration and invasiveness of breast cancer cells.

Abstract

BACKGROUND:

In breast cancer, the HER2/neu oncoprotein, which belongs to the epidermal growth factor receptor family, 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 adenine nucleotide translocase 2 (ANT2) short hairpin RNA (shRNA)-mediated down-regulation of HER2/neu and inhibitory effects on the PI3K/Akt signaling pathway suppressed migration and invasiveness of breast cancer cells.

METHODS:

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.

RESULTS:

In this study, ANT2 shRNA decreased HER2/neu protein levels by promoting degradation of HER2/neu protein through dissociation from heat shock protein 90 (HSP90). 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 membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) expression, decreased matrix metalloproteinase 2 (MMP2) and MMP9 activity, and suppressed migration and invasion of breast cancer cells.

CONCLUSIONS:

These results indicate that knock-down of ANT2 by 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.

• Authors: Ji-Young Jang, Yoon-Kyung Jeon, Chul-Woo Kim
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 391 (Jul 23 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 20650008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenine Nucleotide Translocator 2
• Elafin
• HSP90 Heat-Shock Proteins
• PI3 protein, human
• RNA, Messenger
• RNA, Small Interfering
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Matrix Metalloproteinases
• Matrix Metalloproteinase 14

Topics

• Adenine Nucleotide Translocator 2 (antagonists & inhibitors, genetics, metabolism)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Movement
• Elafin (genetics, metabolism)
• ErbB Receptors (genetics, metabolism)
• Female
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Immunoprecipitation
• Matrix Metalloproteinase 14 (genetics, metabolism)
• Matrix Metalloproteinases (genetics, metabolism)
• Neoplasm Invasiveness
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Messenger (genetics)
• RNA, Small Interfering (pharmacology)
• Receptor, ErbB-2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured