Breast cancer incidence has been increasing over the past 50 years, and is now the second leading cause of death among American women. In an attempt to find the reasons, environmental exposure and dietary factors are being studied. The NF-?B family of transcription factors plays critical roles in many diseases, including cancer, cardiovascular, pulmonary disease, obesity and diabetes. NF-?B factors are sequestered in the cytoplasm in an inactive complex in almost all non-B cells. Surprisingly, aberrant activation of NF-?B was observed in rat mammary tumors induced by the prototypic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and over 95% of primary human breast cancer specimens. Inhibition of NF-?B induced apoptosis or slowed growth, while an MMTV-c-Rel transgenic mouse showed that c-Rel can play a causal role in late onset mammary tumorigenesis. Importantly, mutant Ras and Her-2/neu overexpression, which can be induced by DMBA exposure, were found to activate NF-?B. DMBA activated multiple NF-?B complexes in mouse mammary tumors and in a c-Rel-driven mammary cancer cell line. More recently, the PI's lab has identified a de novo RelB synthesis pathway, shown that RelB promotes epithelial to mesenchymal transition (EMT) of breast cancer, demonstrated that induction of the IKK5/i kinase in human breast tumors and cell lines plays an important role in maintenance of NF-?B activity and transformation, and implicated CK2 in IKK5/i activation. In this revised application, the PI proposes to test the central hypothesis that genetic and epigenetic alterations mediated by environmental carcinogens converge to induce or enhance the activity of multiple NF-?B complexes, thereby promoting a more invasive phenotype of breast cancer cells. Thus, inhibition of NF-?B will revert the malignant phenotype. Cancer epidemiological studies have shown an inverse association between green tea consumption and breast cancer incidence. Green tea is rich in polyphenols (GTPs) with anti-oxidant properties;the most abundant is epigallocatechin-3 gallate (EGCG). EGCG inhibits activation of NF-?B by Her- 2/neu signaling. Recently, green tea or EGCG was shown to reduce the invasive phenotype of DMBA-induced rat mammary tumors and Rel-driven cells in culture, and to slow proliferation of Her-2/neu breast cancer cell lines resistant to trastuzumab. In this revised new RO1 application, three aims are proposed: to (1) elucidate the roles of NF-?B complexes in promoting transformation;(2) elucidate the functional roles of IKK5/i in mammary carcinogenesis and the mechanism of IKK5/i promoter activation;(3) perform pre-clinical animal testing of the ability of GTPs to inhibit growth of Her-2/neu cancers, including those resistant to trastuzumab. Positive findings can readily be translated to the clinic. Important information on the roles of individual NF-?B complexes that are aberrantly activated by environmental carcinogens or oncogenes in promoting invasive breast cancer will be forthcoming;findings should be applicable to wide-spectrum of diseases involving NF-?B.
. This application focuses on the potential role of environmental exposure in the increase in breast cancer incidence in American women, and specifically on a family of nuclear factors (NF-?B family) that have become a target for therapy in a wide spectrum of diseases, including cancer. Carcinogens induce overexpression or mutation in cancer-causing genes that signal via this family of factors, and the PI's group has identified new pathways leading to their expression and shown that green tea components can reverse their activation, even in cells resistant to commonly used therapies. Thus, pre-clinical testing of green tea components on breast cancer cells that are resistant to antibody therapy will be performed, and if successful, this approach can readily be translated to the clinic.
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