NF-kB/Rel is a family of transcription factors known to play important roles in control of expression of genes critical for growth, survival, adhesion, and immune and inflammatory responses. For example, in B lymphocytes, work by the Project Leader has demonstrated NF-kB/Rel factors regulate c-myc oncogene expression, implicated in control of proliferation, neoplastic transformation, and cell survival. In most cells other than B lymphocytes, NF-kB/Rel factors are inactive, sequestered in the cytoplasm. Aberrant activation of NF-kB/Rel in breast cancer has recently been demonstrated by the Project Leader, in collaboration with Dr. A. Rogers. Specifically, human breast tumor cell lines, primary human breast tumor tissue samples, and mammary tumors induced upon carcinogen treatment of rats were found to constitutively express high levels of nuclear NF-kB/Rel, whereas normal rat mammary glands and untransformed breast epithelial cells contained the expected low basal levels. Inhibition of this activity in breast cancer cells in culture led to apoptosis. Furthermore, activation of NF-kB/Rel was found to precede tumor formation in the rat model and during carcinogen-induced in vitro transformation of human mammary epithelial cells. Lastly, the RelA NF-kB subunit and AhR proteins were found to cooperate to induce C-myc expression in breast cancer cells (in collaboration with D. Sherr) and the CK2 kinase was implicated in NF-kB activation (in collaboration with D. Seldin). Thus, the three signaling pathways of NF-kB, AhR and CK2 functionally converge. Here, experiments are proposed to test the hypothesis that aberrant activation of nuclear NF-kB/Rel activity plays a significant role in the pathogenesis of breast cancer.
Specific aims are to: (1) Determine the functional role of aberrant NF-kB/Rel expression in breast cancer cells testing effects on proliferation, viability and neoplastic transformation using cells in culture and transgenic mouse models; (2) Characterize and correlate the time course and nature of NF-kB/Rel activation with disease development and progression; (3) Determine the kinases mediating constitutive NF-kB/Rel activation in breast cancer, including both CK2 and IKK kinases; and (4) Determine the functional role of the c-myc oncogene as a target of NF-kB/Rel activation in the development of breast neoplasias. The roles of AhR and CK2 in modulation of these events will be explored jointly with Projects 1 (Sheir), and 2 (Seldin), respectively. The results of these studies will provide important information on the potential role of aberrant NF-kB/Rel factor expression in the pathogenesis of breast disease, and on its use as a new therapeutic target for treatment modalities of breast disease. Lastly, the potential role of Rel factors as biomarker(s) for analysis of progression of breast disease will be explored.
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