NF-kappaB/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, work by the PI has demonstrated NF-kappaB/Rel factors regulate c-myc oncogene expression, implicated in control of proliferation and neoplastic transformation, as well as promote cell survival in B lymphocytes. In most cells other than B lymphocytes, NF-kappaB/Rel factors are inactive, sequestered in the cytoplasm. Aberrant activation of NF-kappaB/Rel in breast cancer has recently been demonstrated by the PI. 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-kappaB/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 NFkappaB/Rel was found to precede tumor formation in the rat model, and upon carcinogen-induced transformation of human mammary epithelial cells. Here, experiments are proposed to test the hypothesis that aberrant activation of nuclear NF-kappaB/Rel activity plays a significant role in the pathogenesis of breast cancer.
Specific aims are to: 1) Determine the functional role of aberrant NF-kappaB/Rel expression in breast cancer cells testing effects on proliferation, viability and neoplastic transformation using cells in culture and transgenic mouse models; 2) Determine the mechanism of constitutive NF-kappaB/Rel activation in breast cancer; 3) Determine the functional role of the c-myc oncogene as a target of NF-kappaB/Rel activation in development of breast neoplasias. 4) Determine whether aberrant activation of NF-kappaB/Rel occurs prior to neoplastic transformation in human breast disease. The results of these studies will provide important information on the mechanism and role of aberrant NF-kappaB/Rel factor expression in the pathogenesis of breast disease, and on the potential use of these factors as new therapeutic targets in novel treatment modalities of breast disease. Lastly, given the extensive role of Rel factors, the findings of these studies have potential relevance to cancers of other cellular origin, as well as to a wide spectrum of diseases, including AIDS, arthritis, atherosclerosis, and autoimmunity.
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