Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Carcinogenesis (New York), 2000-05, Vol.21 (5), p.871-879

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2000

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.