Carcinogenesis, Vol. 21, No. 5, 871-879,
May 2000
© 2000 Oxford University Press
Cancer Biology |
Activation of NF-
B/Rel occurs early during neoplastic transformation of mammary cells
1 Department of Biochemistry,
2 Department of Pathology and Laboratory Medicine and
3 Program in Research on Women's Health, Boston University Medical School, 715 Albany Street, Boston, MA 02118,
4 Lawrence Berkeley National Laboratory, Berkeley, CA 94720 and
5 Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
NF-
B/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 IBs. We have recently shown that NF-B/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-B/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-B/Rel activation is an early event, occurring prior to malignant transformation. In S–D rats, increased NF-B/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-B (p65/p50). NF-B induction was corrrelated with a decrease in the stability of the NF-B-specific inhibitory protein IB-
. Ectopic expression of the transactivating p65 subunit of NF-B in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF-B elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure, showed dysregulated induction of classical NF-B prior to malignant transformation. Together these findings suggest that activation of NF-B plays an early, critical role in the carcinogen-driven transformation of mammary glands.
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