title: Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells.
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 ERalpha 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O' Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: N
authors.initials: N
authors.lastname: Johnson
authors.forename: J
authors.initials: J
authors.lastname: Bentley
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.forename: C N
authors.initials: CN
authors.lastname: Robson
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: N J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D047428:Protein Kinase Inhibitors; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2