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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-B

Departments of ¹ Biochemistry and ² Environmental Health, Boston University Medical Campus and ³ Women's Health Interdisciplinary Research Center, Boston, Massachusetts

Requests for reprints: Gail E. Sonenshein, Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. Phone: 617-638-4120; Fax: 617-638-4252; E-mail: gsonensh{at}bu.edu.

The aberrant expression of the nuclear factor-B (NF-B) 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-B binding and higher levels of the NF-B transactivating subunits c-Rel, RelA, and RelB, which seemed functional as judged by induction of c-Myc and vimentin, products of two NF-B target genes. Ectopic expression of a super repressor mutant of IB- reduced rel-3983D cell growth and invasive morphology in Matrigel, confirming the role of NF-B 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-B. The aberrant c-Rel expression present in most human breast cancers suggests that this mechanism may play an important role in carcinogenesis. (Cancer Res 2006; 66(5): 2570-5)

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