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)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Geng, Yan; Michowski, Wojciech; Chick, Joel M et al. (2018) Kinase-independent function of E-type cyclins in liver cancer. Proc Natl Acad Sci U S A 115:1015-1020
Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95
Hydbring, Per; Wang, Yinan; Fassl, Anne et al. (2017) Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell 31:576-590.e8
Liu, Lijun; Michowski, Wojciech; Inuzuka, Hiroyuki et al. (2017) G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat Cell Biol 19:177-188
Hydbring, Per; Wang, Yinan; Bogorad, Roman L et al. (2017) Identification of cell cycle-targeting microRNAs through genome-wide screens. Cell Cycle 16:2241-2248
Wang, Haizhen; Nicolay, Brandon N; Chick, Joel M et al. (2017) The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546:426-430
Otto, Tobias; Candido, Sheyla V; Pilarz, Mary S et al. (2017) Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit. Proc Natl Acad Sci U S A 114:10660-10665
Goel, Shom; Wang, Qi; Watt, April C et al. (2016) Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-269
Manterola, Marcia; Sicinski, Piotr; Wolgemuth, Debra J (2016) E-type cyclins modulate telomere integrity in mammalian male meiosis. Chromosoma 125:253-64
Zhang, Jinfang; Xu, Kai; Liu, Pengda et al. (2016) Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt. Mol Cell 62:929-942

Showing the most recent 10 out of 31 publications