title: 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.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada. Electronic address: Jerry.Vriend@med.umanitoba.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vriend
authors.affiliation: Department of Cellular and Structural Biology, UT Health Science Center San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D019313:BRCA1 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D008550:Melatonin / Q000494:pharmacology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D044786:S-Phase Kinase-Associated Proteins; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D008550:Melatonin
keywords: Breast cancer; Estrogen receptor; MCF-7; Melatonin; Ubiquitin ligase