EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTORS .1. BREAST MALIGNANCIES AND OTHER EPITHELIAL PROLIFERATIONS IN TRANSGENIC MICE

BACKGROUND: Growth factors recognized by the epidermal growth factor r eceptor are important in tumor production in some organs. The family o f epidermal growth factor-like growth factors includes a group of poxv iral growth factors: Shope growth factor (SGF), myxoma growth factor M GF), and vaccinia growth factor. These viral growth factors are glycop roteins, whereas all other members of the epidermal growth factor fami ly are proteins. EXPERIMENTAL DESIGN: To understand the potential sign ificance of poxviral growth factors, we made transgenic mice using thr ee different constructs: SGF and MGF cloned downstream from the metall othionein (MT) promoter (MTSGF), and SGF downstream from Rous sarcoma virus long terminal repeat. RESULTS: Founder transgenic mice for each construct were identified, and lines established. Expression of transg enes in MT-SGF mice and MT-MGF mice was induced by feeding animals Zn at 2 months of age. Two months later, both MT-SGF and MT-MGF mice show ed proliferation and arborization of breast ducts and ductules, with s light intraductal proliferation in virgin mice. They also showed gastr ic epithelial hyperplasia, particularly in MT-MGF mice. Stromal and ep ithelial hyperplasia were found in several organs. The transgenes were expressed in epithelia and stroma of breast, lungs, liver and stomach . Rous sarcoma virus long terminal repeat-SGF transgenic mice develope d atypical preneoplastic mammary ductal proliferations in both virgin and nonvirgin females by 6 months of age. In 1/3 of 8-month-old female s, invasive secretory adenocarcinoma developed. These mice also develo ped severe epithelial atypia in the stomach, and papillary gastric tum ors. CONCLUSIONS: Poxviral growth factors may thus be helpful in the s tudy of mammary and gastric oncogenesis and provide insight into growt h factor-induced tumor development.