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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

146 Citations (Scopus)


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 γ-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.

Original languageEnglish
Pages (from-to)1881-1888
Number of pages8
JournalCancer Research
Issue number6
Publication statusPublished - 2008 Mar 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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