TY - JOUR
T1 - Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells
AU - Tominaga, K.
AU - Shimamura, T.
AU - Kimura, N.
AU - Murayama, T.
AU - Matsubara, D.
AU - Kanauchi, H.
AU - Niida, A.
AU - Shimizu, S.
AU - Nishioka, K.
AU - Tsuji, E. I.
AU - Yano, M.
AU - Sugano, S.
AU - Shimono, Y.
AU - Ishii, H.
AU - Saya, H.
AU - Mori, M.
AU - Akashi, K.
AU - Tada, K. I.
AU - Ogawa, T.
AU - Tojo, A.
AU - Miyano, S.
AU - Gotoh, N.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/3/2
Y1 - 2017/3/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84983488771&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983488771&partnerID=8YFLogxK
U2 - 10.1038/onc.2016.293
DO - 10.1038/onc.2016.293
M3 - Article
C2 - 27546618
AN - SCOPUS:84983488771
SN - 0950-9232
VL - 36
SP - 1276
EP - 1286
JO - Oncogene
JF - Oncogene
IS - 9
ER -
