Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer

Elizabeth Iorns, Nicholas C Turner, Richard Elliott, Nelofer Syed, Ornella Garrone, Milena Gasco, Andrew N J Tutt, Tim Crook, Christopher J Lord, Alan Ashworth

Research output: Contribution to journalArticlepeer-review

Abstract

Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.

Original languageEnglish
Pages (from-to)91-104
Number of pages14
JournalCancer Cell
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 2008

Keywords

  • Antineoplastic Agents, Hormonal/pharmacology
  • Breast Neoplasms/drug therapy
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases/metabolism
  • DNA-Binding Proteins/metabolism
  • Drug Resistance, Neoplasm/drug effects
  • Enzyme Activation/drug effects
  • Estrogen Receptor alpha/metabolism
  • Estrogens/deficiency
  • G1 Phase/drug effects
  • Gene Silencing/drug effects
  • Humans
  • Ligands
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Proto-Oncogene Proteins c-raf/genetics
  • RNA, Small Interfering/metabolism
  • Repressor Proteins/metabolism
  • Reproducibility of Results
  • Signal Transduction/drug effects
  • Survival Analysis
  • Tamoxifen/pharmacology
  • Transcription Factors/metabolism
  • Transcription, Genetic/drug effects
  • Transfection

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