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NOTCH3 Signaling Pathway Plays Crucial Roles in the Proliferation of ErbB2-Negative Human Breast Cancer Cells

¹ Consolidated Research Institute for Advanced Science and Medical Care, Departments of ² Applied Chemistry and ³ Life Science and Medical Bioscience, School of Science and Engineering, Waseda University; ⁴ Department of Cellular and Molecular Biology, Institute of Medical Science and ⁵ Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo; ⁶ Department of Clinical Informatics, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University; ⁷ Expression Profiles Team, Biological Information Research Center, National Institute of Advanced Industrial Science and Technology; ⁸ Nippon Gene, Co., Ltd.; and ⁹ Medicrome, Inc., Tokyo, Japan; Departments of ¹⁰ Pathology and ¹¹ Surgical Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan; ¹² Department of Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan; and ¹³ Department of Pathology, Saitama Social Insurance Hospital, Saitama, Japan

Requests for reprints: Kentaro Semba, Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-35449-5278; Fax: 81-35449-5278; E-mail: ksemba{at}waseda.jp.

Key Words: Breast cancer • Cell growth/signaling pathways • Gene amplification • Molecular oncology

ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines. Activated NOTCH1 and NOTCH3 proteins generated by -secretase were detected in most of the cell lines tested, and both proteins activated CSL-mediated transcription. Down-regulation of NOTCH1 by RNA interference had little or no suppressive effect on the proliferation of either ErbB2-positive or ErbB2-negative cell lines. In contrast, down-regulation of NOTCH3 significantly suppressed proliferation and promoted apoptosis of the ErbB2-negative tumor cell lines. Down-regulation of NOTCH3 did not have a significant effect on the ErbB2-positive tumor cell lines. Down-regulation of CSL also suppressed the proliferation of ErbB2-negative breast tumor cell lines, indicating that the NOTCH-CSL signaling axis is involved in cell proliferation. Finally, NOTCH3 gene amplification was detected in a breast tumor cell line and one breast cancer tissue specimen even though the frequency of NOTCH3 gene amplification was low (<1%). Taken together, these findings indicate that NOTCH3-mediated signaling rather than NOTCH1-mediated signaling plays an important role in the proliferation of ErbB2-negative breast tumor cells and that targeted suppression of this signaling pathway may be a promising strategy for the treatment of ErbB2-negative breast cancers. [Cancer Res 2008;68(6):1881–8]