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  • Original Paper
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MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice

Oncogene volume 20, pages 6009–6017 (2001)Cite this article

Abstract

The erbB family of receptor tyrosine kinases is frequently implicated in neoplasia. Amplification and overexpression of erbB2/neu has been found in 20 to 40% of human breast cancers. Previous studies using MMTV/c-neu transgenic mice have linked rat neu overexpression to mammary tumor development. In this study, we provide evidence that rat neu overexpression in mammary tumors of MMTV/c-neu transgenic mice is always associated with demethylation of the MMTV promoter, whereas the normal mammary glands of these transgenic mice always contain specific methylated regions of the MMTV promoter. In addition, after exposure to N-methyl-N-nitrosourea (MNU), the latency of mammary tumor development is significantly reduced and again is also associated with MMTV promoter demethylation. Thus, the transition from methylation to hypomethylation of the MMTV promoter induces high-level expression of c-neu and appears to be a prerequisite for transformation from normal to malignant mammary epithelium, either spontaneously or after carcinogen exposure. Expression of transgenic c-neu from the demethylated MMTV promoter appears to be an early event that allows outgrowth of mammary epithelium predisposed to malignant transformation.

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Acknowledgements

This work was supported by a grant from the National Institute of Health, USA 5R01ES06288. Sanford D Markowitz is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Division of Hematology/Oncology and Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106-4937, Ohio, USA

    Hang Zhou, Wei-dong Chen, Xiusheng Qin, Keunmyoung Lee, Lili Liu, Sanford D Markowitz & Stanton L Gerson

  2. Howard Hughes Medical Institute, Suite 200, 11001 Cedar Road, Cleveland, OH 44106, Ohio, USA

    Sanford D Markowitz

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  1. Hang Zhou
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Correspondence to Stanton L Gerson.

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Zhou, H., Chen, Wd., Qin, X. et al. MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice. Oncogene 20, 6009–6017 (2001). https://doi.org/10.1038/sj.onc.1204830

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