Journal Article

Activation of NF-κB/Rel occurs early during neoplastic transformation of mammary cells

Dong W. Kim, Mika A. Sovak, Gregory Zanieski, Genevieve Nonet, Raphaëlle Romieu-Mourez, Alan W. Lau, Laurie J. Hafer, Paul Yaswen, Martha Stampfer, Adrianne E. Rogers, Jose Russo and Gail E. Sonenshein

in Carcinogenesis

Volume 21, issue 5, pages 871-879
Published in print May 2000 | ISSN: 0143-3334
Published online May 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.5.871
Activation of NF-κB/Rel occurs early during neoplastic transformation of mammary cells

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NF-κB/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 IκBs. We have recently shown that NF-κB/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-κB/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-κB/Rel activation is an early event, occurring prior to malignant transformation. In S–D rats, increased NF-κB/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-κB (p65/p50). NF-κB induction was corrrelated with a decrease in the stability of the NF-κB-specific inhibitory protein IκB-α. Ectopic expression of the transactivating p65 subunit of NF-κB in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF-κB elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure, showed dysregulated induction of classical NF-κB prior to malignant transformation. Together these findings suggest that activation of NF-κB plays an early, critical role in the carcinogen-driven transformation of mammary glands.

Keywords: B[a]P, benzo[a]pyrene; CAT, chloramphenicol acetyltransferase; DMBA, 7,12-dimethylbenz[a]anthracene; EMSA, electrophoretic mobility shift analysis; HMECs, human mammary epithelial cells; PAHs, polycyclic aromatic hydrocarbons; S–D, Sprague–Dawley.

Journal Article.  7824 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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