C-CAM1 is an epithelial adhesion molecule of immunoglobulin supergene family and has been implicated in the growth suppression of prostate cancer cells. Here we show that C-CAM1 can also suppress the tumorigenicity of breast cancer cells. These observations suggest that C-CAM1 may be a general growth suppressor in epithelial cells. In addition, we have identified the cytoplasmic domain, but not the extracellular adhesion domain, of C-CAM1 as critical for the growth suppression. Thus, the adhesion and the growth suppression functions of C-CAM1 are independent of each other. Furthermore, mutation at the tyrosine phosphorylation site in the cytoplasmic domain of C-CAM1 did not obliterate C-CAM1's growth suppression function, suggesting that tyrosine phosphorylation is not involved in the signal transduction pathway leading to cell growth suppression. These studies provide the structural basis for future development of therapeutics that may selectively activate C-CAM1's growth suppression function.