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, Gail E. Sonenshein

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)871-879
Number of pages9
JournalCarcinogenesis
Volume21
Issue number5
Publication statusPublished - 2000

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ASJC Scopus subject areas

  • Cancer Research

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Kim, D. W., Sovak, M. A., Zanieski, G., Nonet, G., Romieu-Mourez, R., Lau, A. W., ... Sonenshein, G. E. (2000). Activation of NF-κB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis, 21(5), 871-879.