Colon cancer is one of the leading causes of mortality in western countries. Whereas much progress has been made to date, in a significant number of cases the molecular mechanisms underlying the initiation of the disease and its progression remain unknown. Bamacan is a newly described chondroitin sulfate proteoglycan that abounds in basement membranes and is also found in the cell nucleus. The applicant recently cloned and characterized the bamacan gene and found that its expression is significantly increased in approx. 70 percent of human colon carcinomas. Aberrant bamacan was also detected in five human colon carcinoma cell lines and in neoplastic tissue of APC Min/+ mice that lack a functional APC tumor suppressor and develop intestinal tumors. Overexpression of bamacan in normal fibroblasts causes transformation, including formation of foci, acquisition of anchorage independent growth and loss of contact inhibition. Bamacan belongs to the Structural Maintenance of Chromosome (SMC) family of proteins and is involved in DNA repair and in the ordered separation of sister chromatids. Alteration of these processes leads to genetic instability and aneuploidy, conditions that can initiate the tumorigenic process. A hypothesis of the proposal is that deregulated expression of bamacan is either initiating transformation or is a secondary event that is necessary for the clonal propagation of the neoplastic cells. A long-term research objective is to elucidate the role of bamacan in the establishment and maintenance of a transformed phenotype. This revised grant proposes to investigate: 1) The transcriptional regulation of the bamacan gene. 2) The functional role of bamacan in tumorigenesis by altering its expression and by assessing the effect of protein mutation using a dominant-negative approach. 3) The contribution of bamacan in vivo to colon tumorigenesis by generating transgenic mice over-expressing bamacan in the intestinal epithelium.
