Identification of novel kinase targets for the treatment of estrogen receptor-negative breast cancer

Clin Cancer Res. 2009 Oct 15;15(20):6327-40. doi: 10.1158/1078-0432.CCR-09-1107. Epub 2009 Oct 6.


Purpose: Previous gene expression profiling studies of breast cancer have focused on the entire genome to identify genes differentially expressed between estrogen receptor (ER) alpha-positive and ER-alpha-negative cancers.

Experimental design: Here, we used gene expression microarray profiling to identify a distinct kinase gene expression profile that identifies ER-negative breast tumors and subsets ER-negative breast tumors into four distinct subtypes.

Results: Based on the types of kinases expressed in these clusters, we identify a cell cycle regulatory subset, a S6 kinase pathway cluster, an immunomodulatory kinase-expressing cluster, and a mitogen-activated protein kinase pathway cluster. Furthermore, we show that this specific kinase profile is validated using independent sets of human tumors and is also seen in a panel of breast cancer cell lines. Kinase expression knockdown studies show that many of these kinases are essential for the growth of ER-negative, but not ER-positive, breast cancer cell lines. Finally, survival analysis of patients with breast cancer shows that the S6 kinase pathway signature subtype of ER-negative cancers confers an extremely poor prognosis, whereas patients whose tumors express high levels of immunomodulatory kinases have a significantly better prognosis.

Conclusions: This study identifies a list of kinases that are prognostic and may serve as druggable targets for the treatment of ER-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / classification
  • Breast Neoplasms / metabolism*
  • Drug Delivery Systems
  • Female
  • Gene Expression Profiling
  • Humans
  • Neoplasms, Hormone-Dependent
  • Receptors, Estrogen / metabolism*
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction


  • Receptors, Estrogen
  • Ribosomal Protein S6 Kinases