Wnt gene family members are thought to play an important role in cell growth and differentiation. When normal wnt gene expression is disrupted, there is the potential for cell transformation. We have found previously that a strong correlation exists between the loss of normal wnt-5a gene expression and cell transformation (Olson and Papkoff, Cell Growth & Differ., 5: 197-206, 1994). Recently, this has been tested directly using antisense wnt-5a, which, when expressed in mouse mammary cells, results in cell transformation (Olson and Gibo, Antisense wnt-5a transforms C57MG mouse mammary epithelial cells, manuscript in preparation). We hypothesize that wnt-5a is a growth-regulating gene, the disruption of which could result in tumorigenesis. The multistage progression of many human cancers involves the loss of normal tumor suppressor gene(s) activity. Several tumor suppressor genes are thought to map to chromosome 3p11-p25. We have studied the ectopic expression of human wnt-5a (3p14-p21) in a tumorigenic uroepithelial cell line with deletion of chromosome 3p13-p21.2. This results in loss of tumorigenicity in athymic nude mice and suppresses anchorage-independent cell growth in soft agar. This suggests that human wnt-5a is a novel tumor suppressor gene in uroepithelial cell carcinoma and may be one of the suppressor genes deleted or rearranged on chromosome 3p.