Carcinogenesis Advance Access published online on August 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn199
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Fibulin-5 Initiates Epithelial-Mesenchymal Transition (EMT) and Enhances EMT Induced by TGF-β in Mammary Epithelial Cells Via a MMP-Dependent Mechanism
Author Affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado 80045
1 Current address: Department of Life Sciences, 600 Chestnut St., Indiana State University, Terre Haute, IN 47809
2 Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado 80045
Corresponding Author: William P. Schiemann, Department of Pharmacology, University of Colorado Health Sciences Center, RC1 South Tower, Room L18-6110, 12801 East 17th Avenue, PO Box 6511, Aurora, Colorado 80045. Phone: (303)724-1541. Fax: (303)724-3663. E-mail: Bill.Schiemann{at}uchsc.edu
Epithelial-mesenchymal transition (EMT) is normal physiological process that regulates tissue development, remodeling, and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis, and cancer cell metastasis. Transforming growth factor-β (TGF-β) is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis. In contrast, malignant MECs typically evolve resistance to TGF-β-mediated cytostasis and develop the ability to proliferate, invade, and metastasize when stimulated by TGF-β. It therefore stands to reason that establishing how TGF-β promotes EMT may offer new insights into targeting the oncogenic activities of TGF-β in human breast cancers. By monitoring alterations in the actin cytoskeleton and various markers of EMT, we show here that the TGF-β gene target, fibulin-5 (FBLN5), initiates EMT and enhances that induced by TGF-β. While normal MECs contain few FBLN5 transcripts, those induced to undergo EMT by TGF-β show significant upregulation of FBLN5 mRNA, suggesting that EMT and the dedifferentiation of MECs overrides the repression of FBLN5 expression in polarized MECs. We also show that FBLN5 stimulated MMP expression and activity, leading to MEC invasion and EMT, to elevated Twist expression, and to reduced E-cadherin expression. Finally, FBLN5 promoted anchorage-independent growth in normal and malignant MECs, as well as enhanced the growth of 4T1 tumors in mice. Taken together, these findings identify a novel EMT and tumor promoting function for FBLN5 in developing and progressing breast cancers.
Key Words: EMT • Fibulin-5 • MMP • Mammary Tumorigenesis • Signal Transduction • TGF-β
* Authors Contributed Equally to this work
Received May 27, 2008; revised August 6, 2008; accepted August 16, 2008.
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