The essential role played by matrix degrading metalloproteinases in tumor invasion and metastasis has become apparent in recent years. Novel concepts of their regulation and function in neoplastic disease are now tenable. Such a concept is that tumor progression in breast cancer could result from the autocrine secretion of transforming growth factor alpba (TGFalpha) by breast cancer cells; this, in turn, stimulates protease synthesis and subsequent degradation of basement membrane and extracellular matrix. It is thought that autoregulatory processes, at the cellular level, are intimately involved in the development and progression of breast cancer. Most breast cancers secrete TGFalpha and express the epidermal growth factor receptor (EGFR). This receptor system has always been viewed as an autocrine system that functions solely to regulate cell proliferation. This view has proven to be incorrect in that most breast cancer cell lines derive no growth regulation from this system. It is possible, therefore, that the TGFalpha/EGFR system may contribute to the malignant progression of breast cancer by altering the pattern of gene expression of metalloproteinases. Degradation of basement membrane by the matrix metalloproteinase stromelysin is a critical step for tumor invasion. We will test the hypotheses that the synthesis, secretion and subsequent action of stromelysin are necessary steps in the cellular invasion and metastasis of human breast cancer and that stromelysin gene expression is regulated by an autocrine mechanism involving TGFalpha. We will generate data that will provide a refinement and elucidation of the problem of breast cancer metastases. This, in turn, will allow a more thorough, long term investigation of the cellular regulation of metalloproteinase gene expression and the role of these proteases in breast cancer metastasis. Our hypothesis will be tested via the following specific aims: 1) We will examine the constitutive expression of the stromelysin genes among breast cancer cell lines and determine if it is modulated by TGFalpha. 2) The specific in vitro and in vivo association of stromelysins with the invasive and metastatic capability of breast cancer cells will be studied. It will be determined if TGFalpha increases these capabilities. 3) Tbe contribution of stromelysins to the malignancy of breast cells will be assessed by transfecting stromelysin DNA into breast cancer cells and the subsequent acquisition of malignant properties will be tested by in vitro assay and growth in nude mice. 4) The autoregulation of stromelysin gene expression by malignant breast epithelial cells will be studied. It will be determined if TGFalpha specifically induces stromelysin gene expression and if the inhibition of EGF receptor signal transduction causes the inhibition of stromelysin induction.
| Heppner, K J; Matrisian, L M; Jensen, R A et al. (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149:273-82 |
