Abstract
Matrix metalloproteinases (MMPs) facilitate cellular invasion by degrading the extracellular matrix, and their regulation is partially dependent on transcription. Binding sites for members of the Ets family of transcription factors are present within MMP promoters and are potent positive regulators. We report a single nucleotide polymorphism at -1607 bp in the MMP-1 promoter, where an additional guanine (G) creates an Ets binding site, 5′-GGA-3′. This polymorphism displays significantly higher transcription in normal fibroblasts and in melanoma cells than the 1 G polymorphism, and it binds substantially more nuclear extract and recombinant ETS-1. Analysis of control DNAs from the Center d'Etude du Polymorphisme Humain pedigrees reveals that this polymorphism is not a mutation, with a frequency of the 2 G polymorphism at 30%. In contrast, in eight tumor cell lines, this frequency increased to 62.5% (P < 0.0001). Thus, this MMP-1 polymorphism contributes to increased transcription, and cells expressing the 2 G polymorphism may provide a mechanism for more aggressive matrix degradation, thereby facilitating cancer progression.
Footnotes
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↵1 Supported by NIH Grants AR-26599 (to C. E. B.) and NS-24279 (to J. F. G.), Grant ST32-CA09658 (to J. L. R.) from the National Cancer Institute, and a grant from the Ronya and Gregory Kozmetsky Foundation (to C. E. B.).
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↵2 To whom requests for reprints should be addressed, at Department of Medicine and Biochemistry, Dartmouth Medical School, Hanover, NH 03755, Phone: (603) 650-1609; Fax: (603) 650-1128; E-mail: c.e.brinckerhoff@dartmouth.edu.
- Received August 27, 1998.
- Accepted October 19, 1998.
- ©1998 American Association for Cancer Research.
Volume 58, Issue 23
