Targeting androgen receptor in estrogen receptor-negative breast cancer

Cancer Cell. 2011 Jul 12;20(1):119-31. doi: 10.1016/j.ccr.2011.05.026.

Abstract

Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%-30% of cases that are ER negative (ER-). Androgen receptor (AR) is expressed in 60%-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER- breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER-/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER-/HER2+ breast cancers.

Publication types

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

MeSH terms

  • Androgens / pharmacology
  • Anilides / pharmacology
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dihydrotestosterone / pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Mice
  • Nitriles / pharmacology
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Androgen / metabolism*
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tosyl Compounds / pharmacology
  • Transcriptional Activation / drug effects
  • Up-Regulation / drug effects
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Xenograft Model Antitumor Assays
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • AR protein, human
  • Androgens
  • Anilides
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Nitriles
  • Receptors, Androgen
  • Receptors, Estrogen
  • Tosyl Compounds
  • Wnt Proteins
  • beta Catenin
  • Dihydrotestosterone
  • bicalutamide
  • ERBB2 protein, human
  • Receptor, ErbB-2