[HTML][HTML] let-7 regulates self renewal and tumorigenicity of breast cancer cells

F Yu, H Yao, P Zhu, X Zhang, Q Pan, C Gong, Y Huang… - Cell, 2007 - cell.com
F Yu, H Yao, P Zhu, X Zhang, Q Pan, C Gong, Y Huang, X Hu, F Su, J Lieberman, E Song
Cell, 2007cell.com
Cancers may arise from rare self-renewing tumor-initiating cells (T-IC). However, how T-IC
self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure.
Because miRNAs can regulate cell-fate decisions, we compared miRNA expression in self-
renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-
BT-IC from 1° breast cancers. let-7 miRNAs were markedly reduced in BT-IC and increased
with differentiation. Infecting BT-IC with let-7-lentivirus reduced proliferation, mammosphere …
Summary
Cancers may arise from rare self-renewing tumor-initiating cells (T-IC). However, how T-IC self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure. Because miRNAs can regulate cell-fate decisions, we compared miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-BT-IC from 1° breast cancers. let-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with let-7-lentivirus reduced proliferation, mammosphere formation, and the proportion of undifferentiated cells in vitro and tumor formation and metastasis in NOD/SCID mice, while antagonizing let-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased let-7 paralleled reduced H-RAS and HMGA2, known let-7 targets. Silencing H-RAS in a BT-IC-enriched cell line reduced self renewal but had no effect on differentiation, while silencing HMGA2 enhanced differentiation but did not affect self renewal. Therefore let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target.
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