ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer

被引:90
作者
Hinohara, Kunihiko [1 ]
Kobayashi, Seiichiro [2 ]
Kanauchi, Hajime [3 ]
Shimizu, Seiichiro [4 ]
Nishioka, Kotoe [5 ]
Tsuji, Ei-ichi [5 ]
Tada, Kei-ichiro [5 ]
Umezawa, Kazuo [6 ]
Mori, Masaki [7 ]
Ogawa, Toshihisa [5 ]
Inoue, Jun-ichiro [8 ]
Tojo, Arinobu [2 ]
Gotoh, Noriko [1 ]
机构
[1] Univ Tokyo, Inst Med Sci, Div Syst Biomed Technol, Minato Ku, Tokyo 1088639, Japan
[2] Univ Tokyo, Inst Med Sci, Div Mol Therapy, Adv Clin Res Ctr,Minato Ku, Tokyo 1088639, Japan
[3] Showa Gen Hosp, Dept Breast & Endocrine Surg, Kodaira, Tokyo 1878510, Japan
[4] Showa Gen Hosp, Dept Pathol Diag, Kodaira, Tokyo 1878510, Japan
[5] Univ Tokyo, Grad Sch Med, Dept Breast & Endocrine Surg, Bunkyo Ku, Tokyo 1138655, Japan
[6] Keio Univ, Fac Sci & Technol, Dept Appl Chem, Yokohama, Kanagawa 2238522, Japan
[7] Osaka Univ, Dept Surg Gastroenterol, Suita, Osaka 5650871, Japan
[8] Univ Tokyo, Inst Med Sci, Div Cellular & Mol Biol, Minato Ku, Tokyo 1088639, Japan
关键词
EGF; HER; tumor sphere; cancer stem cells; inflammation; IN-VITRO PROPAGATION; STEM-CELLS; INITIATING CELLS; IDENTIFICATION; TUMORIGENICITY; TRASTUZUMAB; POPULATION; HEREGULIN; GENES;
D O I
10.1073/pnas.1113271109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-kappa B and by expression of I kappa B alpha-Super Repressor (I kappa B alpha SR), a dominant-negative inhibitor for NF-kappa B. Moreover, the overexpression of I kappa B alpha SR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-kappa B pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-kappa B pathway in human breast cancer.
引用
收藏
页码:6584 / 6589
页数:6
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