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Lookup NU author(s): Dr Nicola Johnson, Dr Johanne Bentley, Lan Wang, Emeritus Professor Herbie Newell, Professor Craig RobsonORCiD, Professor Nicola CurtinORCiD
This is the final published version of an article that has been published in its final definitive form by Nature Publishing Group, 2010.
For re-use rights please refer to the publisher's terms and conditions.
BACKGROUND: Cellular proliferation, driven by cyclin-dependent kinases (CDKs) and their cyclin partners, is deregulated in cancer. Anti-estrogens, such as tamoxifen, antagonise estrogen-induced ER alpha transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27(Kip1)-mediated inhibition of CDK2 and growth arrest. We hypothesised that direct inhibition of CDK2 and CDK1 may overcome the major clinical problem of anti-estrogen resistance. METHODS: The cellular effects of CDK2/1 siRNA knockdown and purine-based CDK2/1 inhibitors, NU2058 and NU6102, were measured in anti-estrogen-sensitive and resistant breast cancer cell lines. RESULTS: CDK2 knockdown caused G1 accumulation, whereas CDK1 depletion caused G2/M slowing, and dual CDK1/2 depletion resulted in further G2/M accumulation and cell death in both anti-estrogen-sensitive and resistant cells, confirming CDK2 and CDK1 as targets for breast cancer therapy. In contrast to tamoxifen, which only affected hormone-sensitive cells, NU2058 and NU6102 reduced CDK2-mediated phosphorylation of pRb, E2F transcriptional activity and proliferation, ultimately resulting in cell death, in both anti-estrogen-sensitive and resistant cells. Both drugs caused G2/M arrest, reflective of combined CDK2/1 knockdown, with a variable degree of G1 accumulation. CONCLUSION: These studies confirm the therapeutic potential of CDK2 and CDK1 inhibitors for cancer therapy, and support their use as an alternative treatment for endocrine-resistant breast cancer. British Journal of Cancer (2010) 102, 342-350. doi:10.1038/sj.bjc.6605479 www.bjcancer.com Published online 15 December 2009 (C) 2010 Cancer Research UK
Author(s): Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, Curtin NJ
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
Year: 2010
Volume: 102
Issue: 2
Pages: 342-350
Date deposited: 15/07/2010
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/sj.bjc.6605479
DOI: 10.1038/sj.bjc.6605479
Notes: See Editorial Expression of Concern (2024) https://doi.org/10.1038/s41416-024-02813-5
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