Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation

The epidermal growth factor receptor (EGFR) is overexpressed in about 48% o f human breast cancer tissues. To analyse the role of the EGFR in mammary t umor development me generated transgenic mice expressing the human EGFR und er the control of either the MMTV-LTR (MHERc) or the beta-lactoglobulin pro moter (BLGHERc), The BLGHERc-transgene was expressed exclusively in the fem ale mammary. gland, whereas the MHERc transgene was expressed more promiscu ously in other organs, such as ovary, salivary gland and testis, Female vir gin and lactating transgenic mice of both strains have impaired mammary gla nd development. Virgin EGFR transgenic mice developed mammary epithelial hy perplasias, whereas in lactating animals progression to dysplasias and tubu lar adenocarcinomas was observed. In both strains the number of dysplasias increased after multiple pregnancies. The transgene expression pattern mas heterogeneous, but generally restricted to regions of impaired mammary glan d development. Highest EGFR transgene expression was observed in adenocarci nomas. By using a whole mount organ culture sa stem to study the differenti ation potential of the mammary epithelium, we observed a reduced number of fully developed alveoli and a decrease in whey acidic protein expression. T aken together, EGFR overexpression results in a dramatic effect of impaired mammary gland development in vitro as well as in vitro, reducing the diffe rentiation potential of the mammary epithelium and inducing epithelial cell transformation.