Carcinogenesis Advance Access originally published online on August 19, 2008
Carcinogenesis 2008 29(12):2243-2251; 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
Department of Pharmacology
1 Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA
2 Present address: Department of Life Sciences, 600 Chestnut Street, Indiana State University, Terre Haute, IN 47809, USA
* To whom correspondence should be addressed. Department of Pharmacology, University of Colorado Health Sciences Center, RC1 South Tower, Room L18-6110, 12801 East 17th Avenue, PO Box 6511, Aurora, CO 80045, USA. Tel: +1 303 724 1541; Fax: +1 303 724 3663; Email: bill.schiemann{at}uchsc.edu
Epithelial–mesenchymal transition (EMT) is a 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. Whereas normal MECs contain few FBLN5 transcripts, those induced to undergo EMT by TGF-β show significant upregulation of FBLN5 messenger RNA, suggesting that EMT and the dedifferentiation of MECs override the repression of FBLN5 expression in polarized MECs. We also show that FBLN5 stimulated matrix metalloproteinase 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.
Abbreviations: ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; FBLN5, fibulin-5; GFP, green fluorescent protein; LOX, lysyl oxidase; MEC, mammary epithelial cell; MMP, matrix metalloproteinase; PCR, polymerase chain reaction; TGF-β, transforming growth factor-β
These authors contributed equally to this work. Received May 27, 2008; revised August 6, 2008; accepted August 16, 2008.
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