Breast cancer metastasis is the leading cause of cancer deaths in women aged 45-65. We have developed an animal tumor model for mammary carcinoma metastasis that closely mimicks human breast carcinoma in its pathology, biochemistry, and pathogenesis of metastasis. We have selected and double cloned variant tumor cell lines capable of spontaneous metastasis from mammary fat pad s.c. sites to regional lymph nodes, bones and lungs in F344 rats. These cloned cell lines undergo reproducible phenotypic drift in malignant and other tumor cell properties and defined passage numbers. We have identified and isolated a cell surface glycoprotein from these cells, the expression of which correlates with spontaneous metastasis. We will now characterize this molecule (gp580), generate specific immunologic reagents against it, and determine its role in spontaneous metastasis. We have also found that highly metastatic cells display changes in the amounts of other glycoconjugates. These molecules will be isolated, characterized, and their role in metastasis determined. Other properties, such as cell adhesion components involved in endothelial and subendothelial matrix interactions, will be identified and studied, as well as degradative enzymes, such as collagenase (IV), thought to be involved in tumor invasive properties. Finally, the role of specific oncogenes in enhancing the instability of tumor cells and increasing the rates at which tumor cell variants are generated ('tumor diversity') will be tested by insertion of different oncogenes or control genes into essentially 'benign' clones of the 13762NF system using retrovirus vectors. Generation of diversity will be examined by subcloning at various time and determining tumor cell properties, including sensitivities to various therapeutic agents.
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