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; H Saya; M Mori; K Akashi; K-I Tada; T Ogawa; A Tojo; S Miyano; N Gotoh

doi:10.1038/onc.2016.293

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

Oncogene. 2017 Mar 2;36(9):1276-1286. doi: 10.1038/onc.2016.293. Epub 2016 Aug 22.

Authors

K Tominaga^{1

2}, T Shimamura³, N Kimura¹, T Murayama^{1

4

5}, D Matsubara⁶, H Kanauchi⁷, A Niida³, S Shimizu⁸, K Nishioka⁹, E-I Tsuji⁹, M Yano¹⁰, S Sugano⁵, Y Shimono¹¹, H Ishii¹², H Saya¹³, M Mori¹⁴, K Akashi¹⁵, K-I Tada⁹, T Ogawa⁹, A Tojo¹, S Miyano³, N Gotoh^{1

4}

Affiliations

¹ Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
² Fellow of the Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.
³ Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
⁴ Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
⁵ Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Science, University of Tokyo, Minato-ku, Tokyo, Japan.
⁶ Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
⁷ Department of Breast and Endocrine Surgery, Showa General Hospital, Kodaira, Tokyo, Japan.
⁸ Department of Pathological Diagnosis, Showa General Hospital, Kodaira, Tokyo, Japan.
⁹ Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
¹⁰ Department of Surgery, Minami machida Hospital, Machida, Tokyo, Japan.
¹¹ Division of Molecular and Cellular Biology, Kobe University, Graduate School of Medicine, Kobe, Japan.
¹² Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹³ Division of Gene Regulation, Institute of Advanced Medical Research, Graduate School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
¹⁴ Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹⁵ Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

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 IGF1R^high 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Carcinogenesis
Female
Gene Expression Regulation, Neoplastic*
Humans
Inhibitor of Differentiation Protein 1 / genetics
Inhibitor of Differentiation Protein 1 / metabolism*
Insulin-Like Growth Factor I / genetics
Insulin-Like Growth Factor I / metabolism
Insulin-Like Growth Factor II / genetics
Insulin-Like Growth Factor II / metabolism*
Mice
Mice, Nude
NF-kappa B / genetics
NF-kappa B / metabolism
Neoplasm Grading
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / metabolism
Neoplasm Recurrence, Local / pathology*
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Phosphatidylinositol 3-Kinase / genetics
Phosphatidylinositol 3-Kinase / metabolism
Prognosis
Signal Transduction
Spheroids, Cellular
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
ID1 protein, human
IGF2 protein, human
Inhibitor of Differentiation Protein 1
NF-kappa B
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Phosphatidylinositol 3-Kinase