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HER2/neu antisense targeting of human breast carcinoma

Oncogene volume 19, pages 6138–6143 (2000)Cite this article

Abstract

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.

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Acknowledgements

Supported by grants from the NIH (CA09141), the Department of Defense Breast Cancer Research Program (BC980871) and the Siteman Cancer Center to JA Drebin. H Roh is the recipient of a post-doctoral training award from the Susan Komen Foundation. C Boswell, D Green, C Hirose and N Mokadam have been supported by NIH training grant T32-CA09621.

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Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, Missouri, USA

    Haeri Roh, James A Pippin, Douglas W Green, Craig B Boswell, Christopher T Hirose, Nahush Mokadam & Jeffrey A Drebin

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  1. Haeri Roh
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Roh, H., Pippin, J., Green, D. et al. HER2/neu antisense targeting of human breast carcinoma. Oncogene 19, 6138–6143 (2000). https://doi.org/10.1038/sj.onc.1204001

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