Identification of a novel C-terminally truncated estrogen receptor α variant (ERαi34) with constitutive transactivation and estrogen receptor antagonist resistance

Mol Cell Endocrinol. 2020 Mar 1;503:110693. doi: 10.1016/j.mce.2019.110693. Epub 2019 Dec 24.

Abstract

Constitutively active estrogen receptor α (ERα) variants with C-terminal truncation are candidate molecules for gain of both endocrine- and chemotherapy-resistance in estrogen-sensitive tumors. Our previous reports using artificially truncated ERα constructs demonstrated that ERα variants encoded in 1-2-3-cryptic exon- and 1-2-3-4-cryptic exon-types of transcripts have potentials to display constitutive transactivation of an estrogen response element reporter. However, naturally occurring 1-2-3-cryptic exon-type ERα variants have not been cloned yet. Therefore, the present study was designed to identify naturally occurring ERα variants encoded in 1-2-3-cryptic exon-type ERα transcripts. We cloned a novel C-terminally truncated ERα variant (ERαi34) encoded in a 1-2-3-i34 transcript from MCF-7 cells and characterized its constitutive and ER antagonist-resistant transactivation in transfected cells. Stable transfection of the variant into MCF-7 cells augmented basal cell proliferation insensitive to fulvestrant. Collectively, we validated the structure-based mechanisms underlying constitutive and ER antagonist-resistant transactivation by C-terminally truncated ERα variants.

Keywords: Alternative splicing; Chemotherapy resistance; ESR1; Endocrine resistance; Splice variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Drug Resistance / genetics*
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor Antagonists / therapeutic use
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Protein Binding / genetics
  • Protein Domains / genetics
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Response Elements / drug effects
  • Response Elements / genetics
  • Transcriptional Activation / genetics*

Substances

  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • Protein Isoforms
  • estrogen receptor alpha, human