The study of "Cyclin E Expression in Human Breast Cancer" seeks to extend our studies of the role of cyclin E and the cell cycle inhibitor p27kip1 in human cancer for 3 additional years. Over the past grant period, we evaluated archival breast tissue samples from 913 young women diagnosed with invasive breast cancer and from 225 women diagnosed with ductal carcinoma in situ (DCIS) for expression of cyclin E and the cell cycle inhibitor p27 in the context of other tumor characteristics, clinical presentation and clinical outcome. In the continuation of this project, we propose a) determine the association of p27 and cyclin with survival at 7 and 10 years as these data become available, and incorporate analyses of the modifying effect of specific therapeutic regimens on survival with respect to cell cycle abnormalities, and b) complete the analysis of the data from women with DCIS to determine the association of cell cycle regulatory proteins and recurrence of disease. We also propose to expand the study to include evaluation of cyclin E and p27 and potential mediators of p27 and/or cyclin E (c-myc, an oncogene that appears to cooperate with p27 in tumorigenesis; cullin-3, a newly identified gene product that targets cyclin E for degradation; and centrosome abnormalities detected by pericentrin immunohistochemistry) in 2 additional groups of women: 1) breast tumors from 576 women unselected for age at diagnosis and 2) tumors from 173 women with HPV-related adenocarcinoma of the cervix. These new study populations will allow us to examine the association between p27 and cyclin E and breast cancer survival in a group of women unselected for age, and in a second tumor type that may exhibit different patterns of cell cycle expression due to the involvement by human papilloma virus (HPV). Considerable evidence is developing that indicates abnormalities of cyclin E and p27 are associated with the initiation and progression of human cancer. It is not known if loss of p27 expression or overexpression of cyclin E are causal, or what role regulators of their expression and degradation play in tumorigenesis. We are developing profiles of cycle regulatory proteins that have the potential to stratify patients into prognostically relevant categories As the genes and the protein products that cooperate with, or regulate the known cell cycle regulatory proteins, are identified and evaluated in sufficient numbers of tumor samples, we will be better able to inform the development of targeted treatment strategies.
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