Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells

N. Johnson, J. Bentley, L. Z. Wang, D. R. Newell, C. N. Robson, G. I. Shapiro, N. J. Curtin

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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 ERα 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.

Original languageEnglish
Pages (from-to)342-350
Number of pages9
JournalBritish Journal of Cancer
Volume102
Issue number2
DOIs
StatePublished - Jan 2010

Keywords

  • Antineoplastic Agents/pharmacology
  • Breast Neoplasms
  • CDC2 Protein Kinase/metabolism
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cyclin-Dependent Kinase 2/metabolism
  • Estrogen Receptor Modulators/pharmacology
  • Female
  • Humans
  • Protein Kinase Inhibitors/pharmacology

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