title: 7,12-dimethylbenz(a)anthracene treatment of a c-rel mouse mammary tumor cell line induces epithelial to mesenchymal transition via activation of nuclear factor-kappaB.
abstract: The aberrant expression of the nuclear factor-kappaB (NF-kappaB) c-Rel subunit that occurs in many human breast cancers can play a causal role in tumorigenesis as judged by findings with a mouse mammary tumor virus (MMTV)-c-rel transgenic mouse model, in which 31.6% of mice developed one or more mammary tumors after a long latency. Interestingly, none of the cell lines established from the mammary tumors grew in soft agar. To begin to test the hypothesis that a prototypic carcinogen insult can promote a more invasive, mesenchymal phenotype, a cell line established from a MMTV-c-rel mammary tumor rel-3983 was treated in culture with the polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA; rel-3983D cells) or DMSO vehicle (rel-3983V cells). Rel-3983D cells displayed an increased rate of proliferation, displayed growth to a higher cell density, and acquired the ability to grow in soft agar and in Matrigel compared with the parental rel-3983 or vehicle-treated rel-3983V cells. Consistent with a more mesenchymal phenotype, rel-3983D cells showed loss of E-cadherin expression as judged by immunofluorescence microscopy. Compared with control cells, rel-3983D displayed increased NF-kappaB binding and higher levels of the NF-kappaB transactivating subunits c-Rel, RelA, and RelB, which seemed functional as judged by induction of c-Myc and vimentin, products of two NF-kappaB target genes. Ectopic expression of a super repressor mutant of IkappaB-alpha reduced rel-3983D cell growth and invasive morphology in Matrigel, confirming the role of NF-kappaB in epithelial to mesenchymal transition (EMT). Thus, DMBA treatment of c-Rel-transformed mammary tumor cells in culture is shown here for the first time to result in EMT via activation of NF-kappaB. The aberrant c-Rel expression present in most human breast cancers suggests that this mechanism may play an important role in carcinogenesis.
authors.affiliation: Department of Biochemistry and Environmental Health, Boston University Medical Campus, Massachusetts 02118, USA.
authors.forename: Sangmin Ryan
authors.initials: SR
authors.lastname: Shin
authors.forename: Nuria
authors.initials: N
authors.lastname: Sánchez-Velar
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
authors.forename: Gail E
authors.initials: GE
authors.lastname: Sonenshein
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D018196:Carcinoma, Adenosquamous / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020573:Genes, rel; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015820:Cadherins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D000072000:NF-KappaB Inhibitor alpha; D015127:9,10-Dimethyl-1,2-benzanthracene