Epidermal growth factor-like growth factors. I. Breast malignancies and other epithelial proliferations in transgenic mice.

BACKGROUND

Growth factors recognized by the epidermal growth factor receptor are important in tumor production in some organs. The family of epidermal growth factor-like growth factors includes a group of poxviral growth factors: Shope growth factor (SGF), myxoma growth factor MGF), and vaccinia growth factor. These viral growth factors are glycoproteins, whereas all other members of the epidermal growth factor family are proteins.

EXPERIMENTAL DESIGN

To understand the potential significance of poxviral growth factors, we made transgenic mice using three different constructs: SGF and MGF cloned downstream from the metallothionein (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 transgenes 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 showed proliferation and arborization of breast ducts and ductules, with slight intraductal proliferation in virgin mice. They also showed gastric epithelial hyperplasia, particularly in MT-MGF mice. Stromal and epithelial 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 developed atypical preneoplastic mammary ductal proliferations in both virgin and nonvirgin females by 6 months of age. In 1/3 of 8-month-old females, invasive secretory adenocarcinoma developed. These mice also developed severe epithelial atypia in the stomach, and papillary gastric tumors.

CONCLUSIONS

Poxviral growth factors may thus be helpful in the study of mammary and gastric oncogenesis and provide insight into growth factor-induced tumor development.