Promotor Regions Determining Over-Expression of Metalloproteinase Genes in Breast Cancer

摘要

The aim of this project is to identify the molecular basis for the abnormal destruction of extracellular matrix that accompanies breast cancer. This is being addressed primarily by identifying the control elements within the genes of the matrix metalloproteinases (MMPs) that drive their high level of expression. It was found that the primary source of MMPs in a breast cancer cell population is the metaplastic cells, which we have demonstrated to have undergone an epithelial-mesenchymal transition. By absolute quantitation of MRNAs, it can be said that the stromelysin-1 and collagenase-3 mRNAs are major gene products of these cells. To make the MMPs, the metaplastic cells require stimulation by a factor secreted by the carcinoma cells that have retained epithelial characteristics. Using metaplastic cells stably transfected with reporter gene constructs, it was demonstrated that the 1100bp of proximal promoter of the stromelysin-1 gene is sufficient to respond to the epithelial- derived inducing factor. A P1 clone contain the gene of another MMP, collagenase-3, has been obtained and is being mapped for DNase hypersensitive sites.