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Loss of metal transcription factor-1 suppresses tumor growth through enhanced matrix deposition

ZISHAN A. HAROON^*, KHALID AMIN, PETER LICHTLEN, BARBARA SATO, NHUNG T. HUYNH, ZHAOHUI WANG, WALTER SCHAFFNER and BRIAN J. MURPHY¹

Biosciences Division, SRI International, Menlo Park, California, USA;
^* Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; and
Institut fur Molekularbiologie der Universitat Zurich, Zurich, Switzerland

¹ Correspondence: Biosciences Division, SRI International, Menlo Park, CA, 94025, USA. E-mail: brian.murphy{at}sri.com

Metal transcription factor-1 (MTF-1) is a ubiquitous transcriptional regulator and chromatin insulator with roles in cellular stress responses and embryonic development. The studies described herein establish for the first time the involvement of MTF-1 in tumor development. Genetically manipulated ras-transformed mouse embryonic fibroblasts (MEFs), wild-type (MTF-1^+/+), or nullizygous for MTF-1 (MTF-1^–/–) were used to develop fibrosarcoma tumors. Loss of MTF-1 resulted in delayed tumor growth associated with increased matrix collagen deposition and reductions in vasculature density. Molecular consequences of MTF-1 loss include increased expression and activation of the transforming growth factor–ß1 (TGF-ß1) and tissue transglutaminase (tTG), two proteins with documented roles in the production and stabilization of extracellular matrix (ECM). Our findings support the hypothesis that MTF-1 enhances the ability of the developing tumor mass to evade fibrosis and scarring of the tumor, a critical step in tumor cell proliferation.—Haroon, Z. A., Amin, K., Lichtlen, P., Sato, B., Huynh, N. T., Wang, Z., Schaffner, W., Murphy, B. J. Loss of metal transcription factor-1 suppresses tumor growth through enhanced matrix deposition.

Key Words: MTF-1 • fibrosis • tumorigenesis

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