Intestinal cancers, particularly those of the colon and rectum, are the second leading cause of cancer death in the United States. Transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR) are frequently overexpressed-by these tumors. A mouse model for human colorectal cancer caused by an inherited mutation in the Apc gene, the Min mouse, will be used to determine whether TGFalpha is a tumor promotion factor for intestinal tumors. The levels of TGFalpha and EGFR RNA and protein expression in intestinal tumor and normal tissue sections will be determined and compared. Min mice lacking TGFalpha will be analyzed to determine whether TGFalpha is necessary for tumor establishment or progression. Min mice carrying an inducible TGFalpha transgene will be analyzed to determine whether TGFalpha overexpression is sufficient to promote tumor establishment or progression. These mice will be analyzed further to determine whether TGFalpha can act as paracrine tumor promotion factor in vivo. The results of these analyses should apply to human intestinal tumors derived from a germline mutation in APC, and might apply to all human colorectal cancers, which usually show somatic loss of APC.
