title: let-7 regulates self renewal and tumorigenicity of breast cancer cells.
abstract: 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.
authors: Department of Breast Surgery, No. 2 Affiliated Hospital, Sun-Yat-Sen University, Guangzhou 510120, People's Republic of China.
authors: Fengyan
authors: F
authors: Yu
authors: Herui
authors: H
authors: Yao
authors: Pengcheng
authors: P
authors: Zhu
authors: Xiaoqin
authors: X
authors: Zhang
authors: Qiuhui
authors: Q
authors: Pan
authors: Chang
authors: C
authors: Gong
authors: Yijun
authors: Y
authors: Huang
authors: Xiaoqu
authors: X
authors: Hu
authors: Fengxi
authors: F
authors: Su
authors: Judy
authors: J
authors: Lieberman
authors: Erwei
authors: E
authors: Song
mesh_terms: 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
chemical_list: D025743:HMGA2 Protein; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras)