Proeolytic Processing of Cyclin E in Breast Cancer

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DESCRIPTION (provided by applicant): Triple negative breast cancer (TNBC) is a highly aggressive subset of invasive breast cancer, accounting for approximately 15% of all cases and defined by lack of estrogen receptor, progesterone receptor, and HER2. Improvements in the treatment of TNBC patients will likely come from identifying the oncogenes critical to the development and maintenance of TNBC. Most importantly, new therapies must treat not only the proliferative population of tumor cells, but also latent populations of disseminated tumor initiating cells, which are hypothesized to be responsible for recurrence and metastasis. Our past work has established important roles for cell cycle regulatory proteins in the initiation and proliferation of tumors in the mammary gland, with an emphasis on the low molecular weight forms of cyclin E (LMW-E). Recent work in our laboratory has demonstrated that LMW-E forms are overexpressed in 70% of TNBCs and correlates with poor prognosis in these patients. We identified novel ways in which LMW-E functions beyond tumor initiation and deregulated proliferation, demonstrating that LMW-E has a role tumor progression. Specifically, we have identified roles for LMW-E in the initiation of the epithelial-mesenchymal transition (EMT), generation of metastases in transgenic mice, and enrichment of a tumor initiating population of cells. The next challenge is to develop a mechanistic understanding of LMW-E in these processes and determine the feasibility of therapeutic attenuation of LMW-E activity in blocking tumor progression. However, we do not know if deregulation of pathways upstream of EL cyclin E is the initiating event. One of the key proteins that is upstream of cyclin E is elastase, which cleaves EL cyclin E to generate LMW-E. An unanswered question is if the deregulation of elastase in tumor cells is sufficient to generate LMW-E giving rise to the transformed phenotype. The central hypothesis of the proposed research is that proteolytic processing of EL cyclin E to LMW-E by elastase predisposes mammary epithelium to oncogenesis by altering cyclin E interacting partners and substrates and aberrantly activating signaling pathways that lead to induction of the EMT and cells with tumor initiating potentials. The following aims are designed to test each aspect of this hypothesis: Aim 1: Determine the requirement of LMW-E timing and expression for tumor maintenance and recurrence in an inducible transgenic mouse model and correlate with TNBC patients. Aim 2: Investigate the role of proteolytic processing of full length cyclin E to LMW-E by elastase in mammary tumorigenesis. Aim 3: Examine the mechanism of LMW-E mediated oncogenecity through identification and characterization of novel binding proteins and substrates for cytoplasmic LMW-E The successful completion of these studies will develop a mechanistic view of consequences of LMW-E expression in tumorigenesis and translate our findings to clinic. Additionally, our mouse model system will provide us with a unique system to examine the effectiveness of novel therapeutics targeted to TNBC in a preclinical in vivo setting.