Breast cancer cells: Modulation by melatonin and the ubiquitin-proteasome system - A review

Jerry Vriend, Russel J Reiter

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Melatonin inhibits human breast cancer cells stimulated with estrogen. This antiproliferative action depends on the presence of the estrogen receptor alpha (ERα) in the human MCF-7 cell line and is strictly dose-dependent. Since researchers concerned with melatonin and breast cancer have not considered the relevance of the ubiquitin-proteasome system to this research in this review we do so. The fact that the first breast cancer susceptibility gene to be identified, Brca1, functions as a ubiquitin ligase indicates that the ubiquitin-proteasome system has a role in regulating susceptibility to breast cancer. While mutations of this gene increase the incidence of breast cancer, the wild type gene suppresses estrogen-dependent transcriptional events relying on the estrogen receptor ERα. Three other ubiquitin ligases, SCFSkp2, E6AP and APC, interact directly with ERα at the ERE and AP-1 promoters of ERα target genes. Melatonin, like proteasome inhibitors, decreases estrogen-induced gene transcription. Indeed, it has been reported that melatonin specifically inhibits estrogen-induced transcription mediated by ERα at the ERE and AP1 gene promoters. Herein, we present a model in which the inhibitory action of melatonin on MCF-7 cells is mediated, directly or indirectly, by the ubiquitin-proteasome system. In this model ERα, apoptotic proteins, and cell cycle proteins, all influenced by melatonin, are substrates of key ubiquitin ligases including SCFSkp2, E6AP, and SCFB-TrCP. Since dysfunction of the ubiquitin-proteasome system is a risk factor for breast cancer, this model provides a context in which to test the clinical potential, and limitations, of melatonin and proteasome inhibitors.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalMolecular and Cellular Endocrinology
Volume417
DOIs
Publication statusPublished - Dec 5 2015

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Keywords

  • Breast cancer
  • Estrogen receptor
  • MCF-7
  • Melatonin
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry

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