"Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells".

Shimono Y ¹, Zabala M ¹, Cho RW ¹, Lobo N ¹, Dalerba P ¹ , Qian D ¹, Diehn M ¹, Liu H ¹, Panula SP ¹, Chiao E ¹, Dirbas FM ², Somlo G ³, Reijo Pera RA ¹, Lao K ⁴, and Clarke MF ¹,

¹ Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304, USA
² Department of Surgery, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
³ City of Hope Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA
⁴ Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404, USA

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Summary:

Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells invitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs invivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells.

Preview:
"MicroRNAs and Parallel Stem Cell Lives":

Peter B. Dirks ¹,

¹ Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada

Summary:

A new study by Shimono et al. (2009) demonstrates that certain microRNAs that regulate the self-renewal factor BMI1 are downregulated in purified populations of normal mammary epithelial stem cells and breast tumor-initiating cells. These findings have important implications for the regulation of self-renewal and differentiation by microRNAs and suggest new ways of targeting cancer stem cells.

Figure 1. MicroRNAs Target BMI1 to Block Self-Renewal

MicroRNA-200c (miR-200c) shows decreased expression in breast cancer stem cells compared to cancer cells in the bulk tumor. Normal mammary epithelial stem cells show lower expression of miR-200c than differentiated cells. It is possible that miR-200c blocks stem cell self-renewal by targeting the 3?UTR of the self-renewal gene BMI1, resulting in loss of BMI1 protein,and attenuation of the ability of cancer stem cells to self-renew and form tumors.

"let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells".

Fengyan Yu1,2, Herui Yao1, Pengcheng Zhu2, Xiaoqin Zhang1, Qiuhui Pan1, Chang Gong1, Yijun Huang3, Xiaoqu Hu1, Fengxi Su1, Judy Lieberman2,  ,and Erwei Song1,

1 Department of Breast Surgery, No. 2 Affiliated Hospital, Sun-Yat-Sen University, Guangzhou 510120, People's Republic of China
2 Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
3 Department of Pharmacology, Zhongshan School of Medicine, Sun-Yat-Sen University, Guangzhou, 510089, People's Republic ofChina

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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70: miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer.
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73: Endogenous human microRNAs that suppress breast cancer metastasis.
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80: MicroRNA signatures in human ovarian cancer.
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