GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells

Mol Cell Endocrinol. 2016 Feb 15:422:160-171. doi: 10.1016/j.mce.2015.11.033. Epub 2015 Dec 13.

Abstract

Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells.

Keywords: Breast cancer; GPER1; IGF-1; IGFBP-1; Tamoxifen.

Publication types

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

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Culture Media, Conditioned / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Female
  • Humans
  • Hydroxytestosterones / pharmacology*
  • Insulin-Like Growth Factor Binding Protein 1 / genetics*
  • Insulin-Like Growth Factor I / pharmacology*
  • MCF-7 Cells
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Estrogen / genetics*
  • Receptors, G-Protein-Coupled / genetics*
  • Signal Transduction / drug effects
  • Tamoxifen / pharmacology*

Substances

  • CREB1 protein, human
  • Culture Media, Conditioned
  • Cyclic AMP Response Element-Binding Protein
  • GPER1 protein, human
  • Hydroxytestosterones
  • IGFBP1 protein, human
  • Insulin-Like Growth Factor Binding Protein 1
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Tamoxifen
  • 4,17 beta-dihydroxy-4-androstene-3-one
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-akt