title: Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells.
abstract: NF-kappaB/Rel is a family of transcription factors which are expressed in all cells; however, in most non-B cells, they are sequestered in the cytoplasm in inactive complexes with specific inhibitory proteins, termed IkappaBs. We have recently shown that NF-kappaB/Rel factors are aberrantly activated in human breast cancer and rodent mammary tumors, and function to promote tumor cell survival and proliferation. Here, we have examined the time-course of induction of NF-kappaB/Rel factors upon carcinogen treatment of female Sprague-Dawley (S-D) rats in vivo and in human mammary epithelial cells (HMECs) in culture. We observed that NF-kappaB/Rel activation is an early event, occurring prior to malignant transformation. In S-D rats, increased NF-kappaB/Rel binding was detected in nuclear extracts of mammary glands from 40% of animals 3 weeks post-treatment with 15 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA); this is prior to formation of tumors which normally begin to be detected after 7-9 weeks. In non-tumorigenic MCF-10F cells, in vitro malignant transformation upon treatment with either DMBA or benzo[a]pyrene (B[a]P) resulted in a 4- to 12-fold increase in activity of classical NF-kappaB (p65/p50). NF-kappaB induction was corrrelated with a decrease in the stability of the NF-kappaB-specific inhibitory protein IkappaB-alpha. Ectopic expression of the transactivating p65 subunit of NF-kappaB in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF-kappaB elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure, showed dysregulated induction of classical NF-kappaB prior to malignant transformation. Together these findings suggest that activation of NF-kappaB plays an early, critical role in the carcinogen-driven transformation of mammary glands.
authors.affiliation: Department of Biochemistry, Department of Pathology and Laboratory Medicine and Program in Research on Women's Health, Boston University Medical School, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Kim
authors.forename: M A
authors.initials: MA
authors.lastname: Sovak
authors.forename: G
authors.initials: G
authors.lastname: Zanieski
authors.forename: G
authors.initials: G
authors.lastname: Nonet
authors.forename: R
authors.initials: R
authors.lastname: Romieu-Mourez
authors.forename: A W
authors.initials: AW
authors.lastname: Lau
authors.forename: L J
authors.initials: LJ
authors.lastname: Hafer
authors.forename: P
authors.initials: P
authors.lastname: Yaswen
authors.forename: M
authors.initials: M
authors.lastname: Stampfer
authors.forename: A E
authors.initials: AE
authors.lastname: Rogers
authors.forename: J
authors.initials: J
authors.lastname: Russo
authors.forename: G E
authors.initials: GE
authors.lastname: Sonenshein
mesh_terms: D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D005260:Female; D016259:Genes, myc; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D016328:NF-kappa B