The incidence of breast cancer has risen over the past 50 years, and it is now the second leading cause ofdeath among American women. In an attempt to find the reasons for this increase in incidence, genetic,environmental and dietary factors are being studied. The NF-KB family of dimeric transcription factors, whichcontrols genes critical for neoplastic transformation, cell proliferation and survival, consists of five members:3 with transactivation domains (c-Rel, RelA, RelB), and 2 without (p50 and p52), which promote strongerbinding. NF-KB factors are sequestered in the cytoplasm in inactive complexes in most cells. Collaborativestudies by members of the Program Project demonstrated constitutive aberrant activation of c-Rel, RelA orp50 NF-KB subunits in -90% of primary human breast cancers, and that exposure to polycyclic aromatichydrocarbons (PAHs), such as 7,12-dimethylbenz(a)anthracene (DMBA) or benzo(a)pyrene, up-regulatedNF-KB in breast cancer. This led us to the central hypothesis in the original application that carcinogens canconstitutively activate NF-KB, which will promote transformation. In collaboration with Projects 1 and 2, wehave more recently shown that NF-KB complexes, which are induced by PAH exposure, play key roles inpromoting an invasive phenotype of breast cancer via epithelial to mesenchymal transition (EMT). (1) PAHexposure of mice activated multiple NF-KB complexes, the IKKe/i kinase and an invasive phenotype of mammarytumors; (2) PAH exposure of c-Rel-driven breast cancer cells further activated NF-KB, which was required for aninvasive phenotype; (3) the c-Rel subunit can play a causal role in mammary tumorigenesis and cooperatedwith protein kinase CK2 to induce the AhR and Slug, a master regulator of EMT; (4) a novel de novo RelBsynthesis pathway was identified, which promoted EMT via induction of Bcl-2; (5) RelB was induced byDMBA or c-Rel and expressed in human breast cancer specimens. Of note, green tea and its polyphenolepigallocatechin-3 gallate (EGCG) reduced invasive phenotype of DMBA-induced mammary tumors andbreast cancer cells. EGCG slowed proliferation of Her-2/neu breast cancer cell lines resistant totrastuzumab, suggesting translational applications of green tea polyphenols. Thus, environmentalcarcinogens are known to induce genetic as well as epigenetic events in mammary tissue. In this revisedrenewal application, we propose to test the hypothesis that these perturbations induce or enhance theactivity of multiple NF-KB complexes thereby promoting a more invasive phenotype of breast cancer: thusinhibition of these pathways will revert the process of EMT.
Three aims are proposed: (1) elucidate the rolesof c-Rel and RelB NF-KB in promoting carcinogenesis; (2) determine the function of IKKe/i in carcinogenesis,and the mechanism of IKKs/i promoter activation; (3) perform pre-clinical in vivo testing of the ability of greentea polyphenols to reduce Her-2/neu-mediated transformation. These studies will provide importantinformation on the mechanisms of activation of aberrant expression of NF-KB factors by environmentalcarcinogens, and characterize their roles in promoting invasive breast cancer. Green tea polyphenols arepotential inhibitors of breast cancer that can readily be translated to the clinic for combinatorial therapies.
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