ERα-targeted endocrine therapy, resistance and the role of GPER

Steroids. 2019 Dec:152:108493. doi: 10.1016/j.steroids.2019.108493. Epub 2019 Sep 10.

Abstract

Endocrine therapy is an effective option for the treatment of estrogen receptor alpha (ERα)-positive breast cancers. Unfortunately, a large fraction of women relapse with endocrine-resistant tumors. The presence of constitutively active ERα mutants, found in a subset of relapse tumors, is thought to be an important endocrine resistance mechanism and has prompted the search for more effective anti-hormone drugs that can effectively inhibit these mutant versions of the receptor. The G protein-coupled estrogen receptor (GPER) is also thought to contribute to the development of endocrine resistance, in part, due to its activation by clinically used selective estrogen receptor modulators and downregulators (SERMs/SERDs). Therefore, next-generation drugs should be screened for potential activity towards GPER. Here, we highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα-positive breast cancers.

Keywords: Breast cancer; ERα; Endocrine resistance; GPER; SERD; SERM.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Estrogen Antagonists / pharmacology*
  • Estrogen Receptor alpha / antagonists & inhibitors*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Antineoplastic Agents, Hormonal
  • ESR1 protein, human
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • GPER1 protein, human
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled