NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.
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.
Yamaguchi
Noritaka
N
Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Japan.
Oyama
Tetsunari
T
Ito
Emi
E
Satoh
Hitoshi
H
Azuma
Sakura
S
Hayashi
Mitsuhiro
M
Shimizu
Ken
K
Honma
Reiko
R
Yanagisawa
Yuka
Y
Nishikawa
Akira
A
Kawamura
Mika
M
Imai
Jun-ichi
J
Ohwada
Susumu
S
Tatsuta
Kuniaki
K
Inoue
Jun-Ichiro
J
Semba
Kentaro
K
Watanabe
Shinya
S
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency* / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D018719:Erb-b2 Receptor Tyrosine Kinases; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C499374:NOTCH3 protein, human