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Lookup NU author(s): Dr Nicola Johnson, Dr Johanne Bentley, Lan Wang, Professor Herbie Newell, Professor Craig Robson, Professor Nicola CurtinORCiD
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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