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Molecular and Cellular Biology, August 2003, p. 5738-5754, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5738-5754.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mouse Mammary Tumor Virus c-rel Transgenic Mice Develop Mammary Tumors

Raphaëlle Romieu-Mourez,1 Dong W. Kim,1 Sang Min Shin,1 Elizabeth G. Demicco,1 Esther Landesman-Bollag,2 David C. Seldin,2 Robert D. Cardiff,3 and Gail E. Sonenshein1*

Departments of Biochemistry,1 Medicine, Boston University Medical School, Boston, Massachusetts 02118,2 UCD Center for Comparative Medicine, University of California, Davis, California 956163

Received 11 November 2002/ Returned for modification 20 February 2003/ Accepted 20 May 2003

Amplification, overexpression, or rearrangement of the c-rel gene, encoding the c-Rel NF-{kappa}B subunit, has been reported in solid and hematopoietic malignancies. For example, many primary human breast cancer tissue samples express high levels of nuclear c-Rel. While the Rev-T oncogene v-rel causes tumors in birds, the ability of c-Rel to transform in vivo has not been demonstrated. To directly test the role of c-Rel in breast tumorigenesis, mice were generated in which overexpression of mouse c-rel cDNA was driven by the hormone-responsive mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter, and four founder lines identified. In the first cycle of pregnancy, the expression of transgenic c-rel mRNA was observed, and levels of c-Rel protein were increased in the mammary gland. Importantly, 31.6% of mice developed one or more mammary tumors at an average age of 19.9 months. Mammary tumors were of diverse histology and expressed increased levels of nuclear NF-{kappa}B. Analysis of the composition of NF-{kappa}B complexes in the tumors revealed aberrant nuclear expression of multiple subunits, including c-Rel, p50, p52, RelA, RelB, and the Bcl-3 protein, as observed previously in human primary breast cancers. Expression of the cancer-related NF-{kappa}B target genes cyclin D1, c-myc, and bcl-xl was significantly increased in grossly normal transgenic mammary glands starting the first cycle of pregnancy and increased further in mammary carcinomas compared to mammary glands from wild-type mice or virgin transgenic mice. In transient transfection analysis in untransformed breast epithelial cells, c-Rel-p52 or -p50 heterodimers either potently or modestly induced cyclin D1 promoter activity, respectively. Lastly, stable overexpression of c-Rel resulted in increased cyclin D1 and NF-{kappa}B p52 and p50 subunit protein levels. These results indicate for the first time that dysregulated expression of c-Rel, as observed in breast cancers, is capable of contributing to mammary tumorigenesis.

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Phone: (617) 638-4120. Fax: (617) 638-4252. E-mail: gsonensh{at}bu.edu.

Molecular and Cellular Biology, August 2003, p. 5738-5754, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5738-5754.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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