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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1091-1103 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2017 |
Funding
We thank the laboratories of Dr. Geoffrey Greene (The University of Chicago), Dr. Charles M. Perou (The University of North Carolina at Chapel Hill), and Dr. Jun Lu (Yale University) for technical support to the project. Dr. Jun Lu provided the miRNA entry clones and the gateway vector backbone. We appreciate the experimental support of several core facilities, including animal facility, optical imaging core facility, integrated microscopy core facility (or the cytometry and imaging microscopy Core), and DNA sequencing facility at the University of Chicago and/or Case Western Reserve University. This study was supported in part by Department of Defense Breast Cancer Research Program W81XWH-09-1-0331 and W81XWH-16-1-0021, Paul Calabresi K12 Award1K12CA139160-02, the University of Chicago Cancer Center Support Grant CA 014599, Case Western Reserve University start-up fund, NIH/NCI K99/R00 CA160638-02, Case Comprehensive Cancer Center Pilot Project P30 CA043703-23, American Cancer Society ACS127951-RSG-15-025-01-CSM, Susan G. Komen Breast Cancer Foundation CCR15332826, Ohio Cancer Research Associates Seeding Grant, Northern Ohio Golf Charities and Foundation, and Case Comprehensive Cancer Center VelaSano Bike for Cure Pilot grant (to H. Liu).
ASJC Scopus subject areas
- General Medicine
