Proteolytic processing of cyclin E in breast cancer

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DESCRIPTION (provided by applicant): In many breast cancers, full length cyclin E is post-translationally modified through elastase mediated proteolytic cleavage of 2 specific sites in the amino terminus, resulting in the generation of low molecular weight (LMW) isoforms that have increased activity in cell cycle and resistance to cyclin-dependent kinase inhibitors. The LMW forms of cyclin E are important because of their significant role as prognostic markers in breast cancer patients and their involvement in cell cycle pathways. Our previous studies have shown that the expression of the LMW forms of cyclin E is observed in 25-35% of patients affected with breast cancer and such expression correlates very strongly with poor clinical outcome. Additionally, we have reported that the LMW forms of cyclin E are functionally hyperactive and resistant to inhibition by p21 and p27. Recently we developed transgenic mice overexpressing the LMW forms of cyclin E in the mammary gland. These mice develop tumors with metastatic potential. The central hypothesis of the proposed research, is that the overexpression of the LMW forms of cyclin E, and not the full-length cyclin E, are directly related to breast cancer progression and metastasis, predisposing the mammary epithelium to oncogenesis. The investigations outlined in this proposal will provide details regarding the mechanism through which the LMW forms of cyclin E mediate their effects in mammary gland tumorigenesis. Specifically, we will: 1) Determine the oncogenic potential of full length cyclin E and the role of elastase cleavage in mediating LMW cyclin E-induced mammary tumors. 2) Identify the biochemical differences between the full length and LMW forms of cyclin E. 3) Investigate the role of CDK2 in breast tumor formation mediated by LMW cyclin E overexpression in the mammary gland, and lastly 4) Determine the requirement of cyclin E for tumor maintenance and recurrence. The proposed research is innovative because it investigates not only whether the LMW forms of cyclin E predispose mammary epithelium to oncogenesis, but also the mechanism by which cyclin E-associated downstream alterations lead to tumor formation in vivo. Collectively, the information gained through the proposed studies could have tremendous clinical relevance for women with early stage and advanced breast cancer. We already know that cyclin E overexpression correlates with poor patient outcome; if cyclin E overexpression also predisposes the mammary gland to genetic instability leading to tumorigenesis it would suggest a causative function for the expression of the LMW forms of cyclin E in breast cancer.