The proliferation of mammalian cells is driven by the core cell cycle machinery operating in cell nucleus. Cyclin-dependent kinases (CDKs) represent key components of this machinery. CDKs act together with their regulatory subunits, cyclins. Cyclin-CDK complexes phosphorylate critical cellular proteins, thereby driving cell cycle progression. Of particular importance for the cancer field are cyclin-CDK complexes which operate during the G1 phase of the cell cycle. During this period, cells either commit to undergo cell division, or exit the cell cycle and enter quiescence. Hence, G1 cyclin-CDK complexes can be regarded as molecular switches which regulate cell proliferation. Indeed, nearly all oncogenic pathways were shown to converge on G1 cyclins and their CDKs. Moreover, gain-of function hyperactivation of G1 cyclins and CDKs represents the driving force of tumor formation in a large number of human cancers. Two classes of cyclins operate during the G1 phase: D-type (cyclins D1, D2 and D3) which activates CDK4 and CDK6, and E-type (cyclins E1 and E2) which activate CDK2 and CDK1. During the past funding period, we made progress in our understanding how the ErbB2 oncogenic pathway impacts the core cell cycle machinery in mouse and human mammary epithelial cells. We found that the ErbB2 signaling impinges on cyclin D1, and requires cyclin D1-CDK4 kinase for initiation of mammary adenocarcinomas. We also found that the continued presence of cyclin D1 protein is required for breast cancer maintenance. We demonstrated that ErbB2 and cyclin D1 are co-overexpressed in a subset of human breast cancers. Importantly, we found that patients bearing these ErbB2+/cyclin D1high breast cancers have particularly poor prognosis (substantially worse than ErbB2+/cyclin D1low, or ErbB2-) with only 13% of patients surviving a 7 year period. In the next funding period we will follow up on these observations and we will rigorously test the utility of targeting individual cyclin-CDK complexes for cancer therapy, using mouse cancer models. We will also study the molecular function played by cyclin-CDK complexes in mouse and human cancer cells. This proposal is aimed at: a) establishing whether cyclin D1-CDK4 kinase is required for breast cancer progression and for metastasis in a MMTV-ErbB2 mouse model and in human breast cancer cells;b) establishing what molecular functions of cyclin-dependent kinases are essential for tumor maintenance;c) testing the utility of inhibiting CDK1 and CDK2 kinase in various mouse cancer models.

Public Health Relevance

Cyclins and their associated cyclin-dependent kinases (CDKs) represent recipients of nearly all oncogenic pathways. Amplification of cyclin or CDK genes and overexpression of their proteins has been documented in a very large number of cancers. For this reason, cyclin-CDK complexes represent potentially very attractive targets for anti-cancer therapy. The proposed work will test the utility of inhibiting specific cyclin- CDK enzymes in cancer treatment, using well-defined mouse models of cancers. Our work will also explore the requirement for cyclin-CDK function in breast cancer metastasis. Hence, this work will lead to better understanding of the roles played by cyclin-CDK complexes in driving human malignancy, and may lead to novel human cancer therapies, centered on inhibition of individual cyclin-CDK complexes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Hildesheim, Jeffrey
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Dana-Farber Cancer Institute
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