We have recently shown that the CSVTCG (cysteine, serine, valine, threonine, cysteine, glycine) sequence of TSP, a natrix protein that has been implicated in mechanisms of malignancy, functions as a tumor cell adhesion domain and CSVTCG peptides as well as anti-CSVTCG antibodies have anti-metastatic activity in a murine model of lung metastasis. We have also isolated a novel CSVTCG-specific tumor cell adhesion receptor and shown by immunohistochemical staining of human breast tumors that the receptor localizes to malignant ductal epithelium while no staining of epithelium in normal and benign tissues was observed. These studies suggest that the CSVTCG-specific receptor may function to promote the invasive behavior of breast epithelium and contribute to the development of malignancy. To test this hypothesis, we propose to retrospectively correlate the expression of the CSVTCG-specific receptor in human breast tumor samples stored in the MCP tumor bank with patient survival and the presence of metastases in patients at time of diagnosis. In addition, we will determine if patients with borderline cancers such as in situ carcinoma and benign tumors with hyperplasia (which expressed receptor) went on to develop malignant disease. Monoclonal antibodies against the CSVTCG-specific receptor will be prepared in order to further characterize the function and structure of the receptor in tumor cell invasion. The primary structure of human and mouse CSVTCG-receptor will be obtained by cloning their cDNA. The receptor structures as they relate to functions will be determined by a) expression of the receptor, b) construction of chimeric and mutated molecules c) and fragmentation of the receptor. The in vitro and in vivo role of the receptor in breast tumor progression will be assessed by studying the characteristics of receptOr (sense and antisense) in transfected normal and neoplastic breast epithelial cells in tissue culture and in athymic mice. These studies should provide information on the role of the CSVTCG-specific thrombospondin receptor in breast cancer tumor progression and whether the expression of the receptor in breast epithelium can be used diagnostically to predict the invasive phenotype.
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