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.
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.
Shin
Sangmin Ryan
SR
Department of Biochemistry and Environmental Health, Boston University Medical Campus, Massachusetts 02118, USA.
Sánchez-Velar
Nuria
N
Sherr
David H
DH
Sonenshein
Gail E
GE
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
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