Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells

K. Tominaga, T. Shimamura, N. Kimura, T. Murayama, D. Matsubara, H. Kanauchi, A. Niida, S. Shimizu, K. Nishioka, E. I. Tsuji, M. Yano, S. Sugano, Y. Shimono, H. Ishii, Hideyuki Saya, M. Mori, K. Akashi, K. I. Tada, T. Ogawa, A. TojoS. Miyano, N. Gotoh

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles’ heels of CSCs, it will be critical to break them for eradication of CSCs.Oncogene advance online publication, 22 August 2016; doi:10.1038/onc.2016.293.

Original languageEnglish
JournalOncogene
DOIs
Publication statusAccepted/In press - 2016 Aug 22

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Tominaga, K., Shimamura, T., Kimura, N., Murayama, T., Matsubara, D., Kanauchi, H., Niida, A., Shimizu, S., Nishioka, K., Tsuji, E. I., Yano, M., Sugano, S., Shimono, Y., Ishii, H., Saya, H., Mori, M., Akashi, K., Tada, K. I., Ogawa, T., ... Gotoh, N. (Accepted/In press). Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. Oncogene. https://doi.org/10.1038/onc.2016.293