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, and Noriko Gotoh
PNAS published ahead of print April 5, 2012 https://doi.org/10.1073/pnas.1113271109

  1. Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved March 8, 2012 (received for review August 15, 2011)

Abstract

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.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: ngotoh{at}ims.u-tokyo.ac.jp

  • Author contributions: K.H. and N.G. designed research; K.H. performed research; S.K., H.K., S.S., K.N., E.-i.T., K.-i.T., K.U., M.M., T.O., J.-i.I., and A.T. contributed new reagents/analytic tools; K.H. analyzed data; and K.H. and N.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1113271109/-/DCSupplemental.

Freely available online through the PNAS open access option.

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ErbB/NF-κB in breast cancer-derived mammospheres
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
Proceedings of the National Academy of Sciences Apr 2012, 201113271; DOI: 10.1073/pnas.1113271109
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