Extracellular Matrix in Breast Cancer Invasion

摘要

The overall goal of our project is to identify novel treatments for breast cancer invasion and metastasis. We view invasion and metastasis as a breakdown of mechanisms that specify tissue organization. We postulated that metastasis is initiated by molecular cues that improperly stimulate cancer cell motility. Therefore, our approach is to block metastasis by understanding, and then interfering with, molecular and cellular mechanisms that regulate cell motility. We found that, in the mammary gland, several of these mechanisms revolve around the interaction of matrix metalloproteinases (MMP) with laminin-5 (Ln-5), an extracellular matrix macromolecule of the breast gland basal lamina. Our major findings are as follows: I) identification of the Ln-5 site onto which cells adhere and migrate; 2) mapping, relative to this cell adhesion site, of a docking site for antibodies that block cell motility; 3) mapping of Ln-5 sites that are cleaved by MMPs; 4) identifying the composition of the Ln-5 fragments resulting from this proteolytic MMP activity. This information should aid the design of reagents for in vivo animal experiments in which to test the ability of antibodies to Ln-5, or Ln-5 fragments, to hopefully block breast cancer cell motility and metastasis.