NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.

Abstract

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 gamma-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.

• Authors: Noritaka Yamaguchi, Tetsunari Oyama, Emi Ito, Hitoshi Satoh, Sakura Azuma, Mitsuhiro Hayashi, Ken Shimizu, Reiko Honma, Yuka Yanagisawa, Akira Nishikawa, Mika Kawamura, Jun-ichi Imai, Susumu Ohwada, Kuniaki Tatsuta, Jun-Ichiro Inoue, Kentaro Semba, Shinya Watanabe
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 6 Pg. 1881-8 (Mar 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18339869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NOTCH3 protein, human
• Receptor, Notch3
• Receptors, Notch
• Receptor, ErbB-2

Topics

• Apoptosis (physiology)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Gene Amplification
• Humans
• RNA Interference
• Receptor, ErbB-2 (deficiency, metabolism)
• Receptor, Notch3
• Receptors, Notch (deficiency, genetics, metabolism)
• Signal Transduction
• Transfection