Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors

Raphaëlle Romieu-Mourez, Dong W. Kim, Sang Min Shin, Elizabeth G. Demicco, Esther Landesman-Bollag, David C. Seldin, Robert D. Cardiff, Gail E. Sonenshein

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Amplification, overexpression, or rearrangement of the c-rel gene, encoding the c-Rel NF-κB 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-κB. Analysis of the composition of NF-κB 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-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)5738-5754
Number of pages17
JournalMolecular and cellular biology
Volume23
Issue number16
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Romieu-Mourez, R., Kim, D. W., Shin, S. M., Demicco, E. G., Landesman-Bollag, E., Seldin, D. C., Cardiff, R. D., & Sonenshein, G. E. (2003). Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Molecular and cellular biology, 23(16), 5738-5754. https://doi.org/10.1128/MCB.23.16.5738-5754.2003