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

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, SCF(Skp2), 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 SCF(Skp2), E6AP, and SCF(B-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.

• Authors: Jerry Vriend, Russel J Reiter
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 417 Pg. 1-9 (Dec 05 2015) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 26363225 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• APC protein, human
• Adenomatous Polyposis Coli Protein
• BRCA1 Protein
• BRCA1 protein, human
• ESR1 protein, human
• Estrogen Receptor alpha
• S-Phase Kinase-Associated Proteins
• UBE3A protein, human
• Ubiquitin-Protein Ligases
• Melatonin

Topics

• Adenomatous Polyposis Coli Protein (genetics)
• BRCA1 Protein (metabolism)
• Breast Neoplasms (metabolism)
• Cell Proliferation (drug effects)
• Estrogen Receptor alpha (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MCF-7 Cells
• Melatonin (pharmacology)
• S-Phase Kinase-Associated Proteins (genetics)
• Transcription, Genetic (drug effects)
• Ubiquitin-Protein Ligases (genetics)