4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) Targets Estrogen Receptor β, to Evoke the Resistance of Human Breast Cancer MCF-7 Cells to G-1, an Agonist for G Protein-Coupled Estrogen Receptor 1

Biol Pharm Bull. 2021;44(10):1524-1529. doi: 10.1248/bpb.b21-00417.

Abstract

Bisphenol A (BPA) has been shown to induce the activation of nuclear estrogen receptor α/β (ERα/β) in both in vitro and in vivo settings. We originally obtained a 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a possible active metabolite of BPA, strongly activating the ERs-mediated transcription in MCF-7 cells with an EC50 of 2.8 nM (i.e., BPA's EC50 = 519 nM). Environmental estrogens can also target G protein-coupled estrogen receptor 1 (GPER1), a membrane-type ER. However, the effects of BPA/MBP on GPER1, have not yet been fully resolved. In this study, we used MCF-7, a ERα/ERβ/GPER1-positive human breast cancer cell line, as a model to investigate the effects of the exposure to BPA or MBP. Our results revealed that at concentrations below 1 nM MBP, but not BPA, downregulates the expression of GPER1 mRNA via upregulated ERβ, and the MCF-7 cells pre-treated with MBP display resistance to GPER1 agonist G-1-mediated anti-proliferative effects. Because GPER1 can act as a tumor suppressor in several types of cancer including breast cancer, the importance of MBP-mediated decrease in GPER1 expression in breast cancer cells is discussed.

Keywords: 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP); G protein-coupled estrogen receptor 1 (GPER1); MCF-7; bisphenol A (BPA).

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cyclopentanes / pharmacology*
  • Cyclopentanes / therapeutic use
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Estrogen Receptor beta / antagonists & inhibitors*
  • Female
  • Humans
  • MCF-7 Cells
  • Phenols / pharmacology*
  • Phenols / therapeutic use
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • Receptors, Estrogen / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects

Substances

  • 1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone
  • 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene
  • Cyclopentanes
  • ESR2 protein, human
  • Estrogen Receptor beta
  • GPER1 protein, human
  • Phenols
  • Quinolines
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled