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HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53

Oncogene volume 22, pages 2910–2919 (2003)Cite this article

Abstract

Transgenic mice, which selectively express the WAP-HBX transgene in mammary gland epithelial cells (ME-cells), were established in order to elucidate the consequences of HBX gene expression on organ differentiation, cell death program and tumor development. Transgene expression was demonstrable by RT–PCR, Northern and Western blot analysis during pregnancy, lactation and after weaning. HBX synthesis neither affect mammary gland differentiation nor apoptosis in ME-cells. Although breast cancer formation was rare in WAP-HBX animals (<1%), WAP-HBX•p53+/− hybrid animals developed breast tumors at an increased rate (12/85) after a latency period of 8–18 months. We also show here for the first time that HBX can immortalize ME-cells generated from mammary gland tissue segments in a p53-independent fashion. HBX causes cyclin D1 gene overexpression during early pregnancy, and this is maintained in ME-cells isolated either from mammary gland or from breast tumors. Intranuclear cyclin D1 accumulation also occurs in the absence of external growth factors and the BrdU incorporation rate remains high under serum starvation conditions. Finally, both cyclin D1 induction and HBX mitotic activity are dependent on p38 and c-Jun N-terminal kinase, but not on MEK-1 kinase activity.

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Acknowledgements

This work was supported by the EUROPEAN COMMISSION BIOMED 2 Programme-PL96-3731 and the Verband der Chemischen Industrie. We thank Dr A Corfield for critical reading of the manuscript.

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Authors and Affiliations

  1. Institut für Molekularbiologie und Biochemie, Freie Universität Berlin, Arnimallee 22, Berlin, 14195, Germany

    Andreas Klein, Eva Guhl, Jutta Fuhrhop, Monika Graessmann & Adolf Graessmann

  2. Graduate Institute of Molecular and Cell Biology, Tzu-Chi University, Hualien, 970, Taiwan, Taiwan

    Yin-Jeh Tzeng

  3. Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome ‘La Sapienza’, Viale del Policlinico 155, Roma, 00161, Italy

    Massimo Levrero

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  1. Andreas Klein
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Klein, A., Guhl, E., Tzeng, YJ. et al. HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53. Oncogene 22, 2910–2919 (2003). https://doi.org/10.1038/sj.onc.1206539

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