The preliminary experiments for this proposal defined a new species of haptoglobin and associated it with tumor invasion, metastasis, and, hence, early recurrence in human breast cancer. The ultimate aim of the proposed studies it to understand more fully the role of this new haptoglobin species in the neoplastic process. This will, it is hoped, be achieved through more extensive biochemical characterization, through additional clinical studies of both neoplastic and neoplastic conditions, and through biologic experimentation, both in vivo and in vitro. Biochemical characterization of the cancer-related haptoglobin will consist of further sequence analysis to define further its relationship to conventional haptoglobin species and a newly discovered related gene, assignment of functions as they are uncovered to specific structural loci, and analysis of subunit composition as well as the factors governing and significance of the observed formation of oligomers. It is hoped that the biochemical studies will permit precise structural-functional correlations to be made, which in turn may further understanding of the role of this protein in tumor biology. The cancer-related haptoglobin is a marker of increased malignant potential. Biologic studies will be undertaken to determine if it is also a mediator of a malignant phenotype. Previous studies suggest that it might act as a component of the extracellular matrix, or as a modulator of the host immune system. These possibilities will be explored with a series of assays in vitro. Additional studies in vivo will be performed to test these hypotheses, and to search for additional effects upon the tumor-host relationship. Finally, antibodies of precisely defined specificity will be prepared to enlarge upon preliminary clinical studies of human breast cancer and to extend the approach to other human neoplasms and normal tissues. The presence of the cancer related haptoglobin will be correlated with outcome. It is hoped that this will lead to a useful diagnostic test in the short run, and to diagnostically and biologically important insights in the long run.
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