Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors.
Whereas the Her2/neu/erbB2 receptor (Her2) could be a molecular target of the receptor-positive breast cancer, the therapeutic targets of Her2-negative cancer largely remain to be established. The expression of Her2 was evaluated in 48 primary breast cancer tumors by immunohistochemistry. The identified Notch pathway was studied in genotoxin-dependent suppression of breast cancer-initiating cell growth. Immunohistochemical assessment of Her2-negative tumors revealed significant association with overexpression of Notch1 and Notch3. Knockdown of Notch pathway resulted in sensitization of breast cancer cells to deionizing radiation, leading to cell death; the effect was more significant in stem marker CD44+ than in CD44- cells, and more profound in the Her2-negative than in positive cancer cells. The present study indicates that inhibition of Notch signaling could antagonize survival signal of Her2-negative breast cancer-initiating cells carrying genomic damage, and suggests that targeted suppression of the Notch pathway may give the rationale for sensitizing Her2-negative cancer-initiating cells to a therapeutic approach.
Hirose
Hajime
H
Department of Gastrointestinal Surgery, Osaka University School of Medicine, Yamadaoka, Osaka, Japan.
Ishii
Hideshi
H
Mimori
Koshi
K
Ohta
Daisuke
D
Ohkuma
Masahisa
M
Tsujii
Hirohiko
H
Saito
Toshiyuki
T
Sekimoto
Mitsugu
M
Doki
Yuichiro
Y
Mori
Masaki
M
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051880:Receptors, Notch