The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer

Curr Opin Pharmacol. 2010 Dec;10(6):620-8. doi: 10.1016/j.coph.2010.09.007.


Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, so called for their ability to function as ER agonists or antagonists depending on the tissue in which they operate. These mechanistic insights have had a significant impact on the discovery of second generation SERMs, some of which are in late stage clinical development for the treatment/prevention of breast cancer as well as other estrogenopathies. In addition to the SERMs, however, have emerged the Selective Estrogen Degraders (SERDs), which as their name suggests, interact with and facilitate ER turnover in cells. One drug of this class, fulvestrant, has been approved as a third line treatment for ER-positive metastatic breast cancer. Whereas the first generation SERMs/SERDs were discovered in a serendipitous manner, this review will highlight how our understanding of the molecular pharmacology of ER ligands has been utilized in the development of the next generation of SERMs/SERDs, some of which are likely to have a major impact on the pharmacotherapy of breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Clinical Trials as Topic
  • Drug Discovery*
  • Drug Partial Agonism
  • Estrogen Receptor Modulators / metabolism
  • Estrogen Receptor Modulators / pharmacology*
  • Female
  • Humans
  • Ligands
  • Molecular Conformation
  • Molecular Targeted Therapy*
  • Nuclear Receptor Coactivators / metabolism
  • Receptors, Estrogen / agonists
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / metabolism*
  • Receptors, Estrogen / therapeutic use
  • Selective Estrogen Receptor Modulators / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology*
  • Signal Transduction
  • Transcriptional Activation


  • Antineoplastic Agents
  • Estrogen Receptor Modulators
  • Ligands
  • Nuclear Receptor Coactivators
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators