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The contribution of a single nucleotide polymorphism to endogenous MMP-1 gene expression, and the contribution of MMP-1 expression to breast cancer cell invasion and tumorigenesis.

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Call No.	Ph.D. 2004
Author	Wyatt, Colby Alan.
Title	The contribution of a single nucleotide polymorphism to endogenous MMP-1 gene expression, and the contribution of MMP-1 expression to breast cancer cell invasion and tumorigenesis.
Date	2004
Abstract	Extra cellular matrix (ECM) provides structural support for the body and also contributes to cell proliferation and migration. Modification ECM is an important part of normal physiology, and integral to a variety of pathologies including tumor growth and progression. Matrix metalloproteinases (MMPs) are a family of greater than 20 enzymes capable of modifying the ECM. In normal physiology MMP expression is tightly regulated at low levels however, high levels of MMP expression are known to contribute to tumor growth and progression. The most widely expressed MMP is MMP-1, and MMP-1 expression is partially regulated by ETS and AP-1 transcription factor binding sites in the proximal MMP-1 promoter. Additionally, a polymorphism consisting of the insertion (2G) or deletion (1G) of a guanine nucleotide has been described at position -1607 bp in the MMP-1 promoter. The 2G polymorphism creates an ETS binding site in close proximity to an AP-1 binding site, and transient transfection assays have demonstrated that 2G MMP-1 promoters are more transcriptionally active than 1G promoters. To understand the contribution of the 2G polymorphism to endogenous MMP-1 expression, primary fibroblast isolates were genotyped for the MMP-1 promoter, stimulated to produce MMP-1, and the MMP-1 mRNA expression levels were correlated with the promoter genotype. In human foreskin fibroblasts, the presence of a 2G polymorphism is not adequate for higher MMP-1 mRNA expression however, there is a greater dispersion of MMP-1 mRNA levels in a series of cells containing a 2G polymorphism, suggesting that the presence of a 2G polymorphism may increase the potential for a cell to have higher MMP-1 expression levels. Higher MMP-1 expression has been correlated with the increased incidence or invasiveness of several cancers. To determine whether MMP-1 contributes to breast cancer tumorigenesis, RNA interference was utilized to silence constitutively high MMP-1 expression in MDA-MB-231 breast cancer cells. Blocking MMP-1 expression in this cell line inhibited cell mediated destruction of a type 1 collagen matrix, and significantly decreased the size of tumors formed by MDA-MB-231 cells injected into the mammary fat pad of nude mice, suggesting MMP-1 expression is important for tumor growth in a murine model of breast tumorigenesis.
Description	x, 108 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Constance E. Brinckerhoff Bradley A. Arrick.
Subject	Genetic polymorphisms. Metalloproteinases -- Genetic aspects. Metalloproteinases -- Pathophysiology. Breast -- Cancer -- Genetic aspects. Carcinogenesis.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.54

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	The contribution of a single nucleotide polymorphism to endogenous MMP-1 gene expression, and the contribution of MMP-1 expression to breast cancer cell invasion and tumorigenesis. A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the Degree of Doctor of Philosophy In Biochemistry By Colby Alan Wyatt DARTMOUTH COLLEGE Hanover, New Hampshire August 16, 2004 Examining Committee: Bradley A. Arrick M.D., Ph.D. (Chair) Constance E. Brinckerhoff, Ph.D. Christopher H. Lowrey M.D. Steven D. Shapiro M.D., Ph.D. Carol Folt Ph.D. Dean of Graduate Studies

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The contribution of a single nucleotide polymorphism to endogenous MMP-1 gene expression, and the contribution of MMP-1 expression to breast cancer cell invasion and tumorigenesis.

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