title: Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors.
abstract: Amplification, overexpression, or rearrangement of the c-rel gene, encoding the c-Rel NF-kappaB 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-kappaB. Analysis of the composition of NF-kappaB 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-kappaB 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-kappaB 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.
authors.affiliation: Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118, USA.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Romieu-Mourez
authors.forename: Dong W
authors.initials: DW
authors.lastname: Kim
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Shin
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Demicco
authors.forename: Esther
authors.initials: E
authors.lastname: Landesman-Bollag
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Gail E
authors.initials: GE
authors.lastname: Sonenshein
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002461:Cell Line, Transformed; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020079:Terminal Repeat Sequences; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D018076:DNA, Complementary; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D051020:bcl-X Protein; D019938:Cyclin D1; D012313:RNA; D004247:DNA; D008156:Luciferases