GPER-induced signaling is essential for the survival of breast cancer stem cells

Int J Cancer. 2020 Mar 15;146(6):1674-1685. doi: 10.1002/ijc.32588. Epub 2019 Aug 7.

Abstract

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.

Keywords: BAD; GPER; breast cancer stem cell; phosphoproteomics; tamoxifen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast / pathology
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Neoplastic Stem Cells / pathology*
  • Phosphorylation / drug effects
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Progesterone / metabolism
  • Signal Transduction / drug effects
  • Spheroids, Cellular
  • Tamoxifen / pharmacology
  • Xenograft Model Antitumor Assays
  • bcl-Associated Death Protein / metabolism

Substances

  • BAD protein, human
  • GPER1 protein, human
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Receptors, Progesterone
  • bcl-Associated Death Protein
  • Tamoxifen
  • Cyclic AMP-Dependent Protein Kinases