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

Kunihiko Hinohara, Seiichiro Kobayashi, Hajime Kanauchi, Seiichiro Shimizu, Kotoe Nishioka, Ei Ichi Tsuji, Kei Ichiro Tada, Kazuo Umezawa, Masaki Mori, Toshihisa Ogawa, Jun Ichiro Inoue, Arinobu Tojo, Noriko Gotoh

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)


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-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR 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-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.

Original languageEnglish
Pages (from-to)6584-6589
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - Apr 24 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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