Evaluation of Cyclooxygenase-2 as a Novel Target for Breast Cancer Prevention
Final rept. 1 Jul 1998-30 Jun 2001
CORNELL UNIV MEDICAL COLL (WEILL) NEW YORK
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The inducible prostaglandin synthase cyclooxygenase-2 Cox-2 is expressed in a variety of human cancers, but its role in breast cancer has not been definitively established. Our research was designed to test whether Cox-2 is important in the pathogenesis of mammary cancer using Wnt-1 as a model mammary oncogene. Wnt-1 transgenic mice exhibit mammary hyperplasia and subsequently develop mammary carcinomas. Additionally, some mouse mammary epithelial cell lines are transformed by Wnt-1 expression. We have demonstrated upregulation of Cox-2 gene transcription in Wnt-1 expressing cell lines, and in mammary tumors from Wnt-1 transgenic mice. Our experiments suggest that Ets family transcription factors contributes to the observed Cox-2 upregulation. Firstly, we have observed that the Ets factor PEA3 is upregulated in response to Wnt-1 expression in C57MG mouse mammary epithelial cells, and PEA3 factors are highly expressed in tumors from Wnt-1 transgenic mice. Secondly, we have demonstrated that PEA3 potently activates transcription of the Cox-2 gene. In addition, we have tested the role of Cox-2 in mammary tumorigenesis by generating Wnt-1 transgenic mice of the following Cox-2 genotypes 1, 1- and -I-, and then evaluating the incidence of mammary hyperplasia and carcinoma formation in these animals. The results of these analyses are described herein.
- Medicine and Medical Research