let-7 regulates self renewal and tumorigenicity of breast cancer cells.
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 degrees 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.
Yu
Fengyan
F
Department of Breast Surgery, No. 2 Affiliated Hospital, Sun-Yat-Sen University, Guangzhou 510120, People's Republic of China.
Yao
Herui
H
Zhu
Pengcheng
P
Zhang
Xiaoqin
X
Pan
Qiuhui
Q
Gong
Chang
C
Huang
Yijun
Y
Hu
Xiaoqu
X
Su
Fengxi
F
Lieberman
Judy
J
Song
Erwei
E
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D005260:Female; D025743:HMGA2 Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000502:physiology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism
D025743:HMGA2 Protein; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras)