Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 417, Issue C, Pages 1-9Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.09.001
Keywords
Melatonin; Breast cancer; MCF-7; Estrogen receptor; Ubiquitin ligase
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Melatonin inhibits human breast cancer cells stimulated with estrogen. This antiproliferative action depends on the presence of the estrogen receptor alpha (ER alpha) 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 ER alpha. Three other ubiquitin ligases, SCFSkp2, E6AP and APC, interact directly with ER alpha at the ERE and AP-1 promoters of ER alpha 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 ER alpha 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 ER alpha, 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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