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Clin Cancer Res. 2017 Feb 15;23(4):1091-1103. doi: 10.1158/1078-0432.CCR-16-0943. Epub 2016 Jul 19.

miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway.

Author information

1
The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
2
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
3
Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
4
Stanford Cancer Institute, Stanford University, Stanford, California.
5
Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
6
Department of Medical Oncology, Hospital Clínic, Universitat de Barcelona, Spain.
7
Department of Health Studies, The University of Chicago, Chicago, Illinois.
8
Department of Mathematics, Statistics and Computer Science, University of Illinois at Chicago, Chicago, Illinois.
9
Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio. hliu@case.edu.
10
The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
11
The National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio.

Abstract

Purpose: Effective targeting of cancer stem cells is necessary and important for eradicating cancer and reducing metastasis-related mortality. Understanding of cancer stemness-related signaling pathways at the molecular level will help control cancer and stop metastasis in the clinic.Experimental Design: By analyzing miRNA profiles and functions in cancer development, we aimed to identify regulators of breast tumor stemness and metastasis in human xenograft models in vivo and examined their effects on self-renewal and invasion of breast cancer cells in vitro To discover the direct targets and essential signaling pathways responsible for miRNA functions in breast cancer progression, we performed microarray analysis and target gene prediction in combination with functional studies on candidate genes (overexpression rescues and pheno-copying knockdowns).Results: In this study, we report that hsa-miR-206 suppresses breast tumor stemness and metastasis by inhibiting both self-renewal and invasion. We identified that among the candidate targets, twinfilin (TWF1) rescues the miR-206 phenotype in invasion by enhancing the actin cytoskeleton dynamics and the activity of the mesenchymal lineage transcription factors, megakaryoblastic leukemia (translocation) 1 (MKL1), and serum response factor (SRF). MKL1 and SRF were further demonstrated to promote the expression of IL11, which is essential for miR-206's function in inhibiting both invasion and stemness of breast cancer.Conclusions: The identification of the miR-206/TWF1/MKL1-SRF/IL11 signaling pathway sheds lights on the understanding of breast cancer initiation and progression, unveils new therapeutic targets, and facilitates innovative drug development to control cancer and block metastasis. Clin Cancer Res; 23(4); 1091-103. ©2016 AACR.

PMID:
27435395
PMCID:
PMC5247402
DOI:
10.1158/1078-0432.CCR-16-0943
[Indexed for MEDLINE]
Free PMC Article

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