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

Oncogene volume 19, pages 2129–2137 (2000)Cite this article

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in about 48% of human breast cancer tissues. To analyse the role of the EGFR in mammary tumor development we generated transgenic mice expressing the human EGFR under the control of either the MMTV-LTR (MHERc) or the β-lactoglobulin promoter (BLGHERc). The BLGHERc-transgene was expressed exclusively in the female mammary gland, whereas the MHERc transgene was expressed more promiscuously in other organs, such as ovary, salivary gland and testis. Female virgin and lactating transgenic mice of both strains have impaired mammary gland development. Virgin EGFR transgenic mice developed mammary epithelial hyperplasias, whereas in lactating animals progression to dysplasias and tubular adenocarcinomas was observed. In both strains the number of dysplasias increased after multiple pregnancies. The transgene expression pattern was heterogeneous, but generally restricted to regions of impaired mammary gland development. Highest EGFR transgene expression was observed in adenocarcinomas. By using a whole mount organ culture system to study the differentiation potential of the mammary epithelium, we observed a reduced number of fully developed alveoli and a decrease in whey acidic protein expression. Taken together, EGFR overexpression results in a dramatic effect of impaired mammary gland development in vitro as well as in vivo, reducing the differentiation potential of the mammary epithelium and inducing epithelial cell transformation.

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Acknowledgements

The authors would like to give their gratitude to Mrs Renate Franke for excellent technical assistance in histology and immunohistochemistry. We thank Drs AJ Clark. (Rosslin Institute, Edinburgh, Scotland), M Treuner (MDC Berlin, Germany) and A Ullrich (Max-Planck-Insitute, Munich, Germany), for providing plasmids, and Dr R Junker (Novartis Inc., Basel, Switzerland) for additional pathological evaluation. Finally we thank Drs B Davies, R Schäfer and DS Salomon for critical reading the manuscript and several discussions promoting to finish the manuscript.

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Author notes

  1. Ralf Brandt

    Present address: Novartis Pharma Inc., Oncology/In vivo Pharmacology, K-125.1145, Postfach, 4002, Basel, Switzerland

  2. Ralf Brandt and Wolfgang Zschiesche: We are sorry to announce that Wolfgang Zschiesche who was responsible for the pathological analysis has unfortunately passed away

Authors and Affiliations

  1. Schering Research Laboratories, Postfach 650311, Berlin, 13342, Germany

    Ralf Brandt, Ralf Eisenbrandt, Carola Juergensen & Franz Theuring

  2. University Hospital Charite, Institute for Pharmacology and Toxicology, Dorotheen Str. 94, Berlin, 10117, Germany

    Frauke Leenders & Franz Theuring

  3. MDC for Molecular Medicine, Robert-Roessle-Str. 10, Berlin, 13122, Germany

    Wolfgang Zschiesche & Bert Binas

  4. Max-Planck-Institute for Molecular Genetics, Ihnestr. 73, Berlin, 14195, Germany

    Ralf Eisenbrandt

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Brandt, R., Eisenbrandt, R., Leenders, F. et al. Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation. Oncogene 19, 2129–2137 (2000). https://doi.org/10.1038/sj.onc.1203520

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