Membrane-bound melatonin receptor MT1 down-regulates estrogen responsive genes in breast cancer cells.
Melatonin possesses anti-estrogenic effects on estrogen receptor expressing (ER+) breast cancer cells in culture by reducing cell cycle progression and cell proliferation. There is increasing agreement that on a cellular level the effects of melatonin are primarily induced by the membrane-bound receptor MT1. The participation of a second, nuclear receptor of the group of ligand-dependent transcription factors, called RZRalpha, is under debate. In this study we used a number of breast cancer cell lines differing in their expression of the estrogen receptor and the two known melatonin receptors. In MCF-7 breast cancer cells transfected with a vector carrying the MT1 gene (MCF-7Mel1a) binding of CREB-protein to the cAMP-responsive element of the breast cancer suppressing gene BRCA-1 was more strongly reduced by treatment with melatonin than in the parental cells. Expression of estrogen responsive genes was determined in serum-starved cells, cells stimulated for 16 hr with estradiol and cells subsequently treated with melatonin. Expression of BRCA-1, p53, p21(WAF) and c-myc were up-regulated by estradiol. Treatment of the stimulated cells with melatonin counteracted the increase induced by estradiol almost completely. The more MT1 a cell line expressed, the stronger was the reduction of the expression of the estradiol-induced genes. There was no correlation between the expression of the nuclear receptor RZRalpha and the effects of melatonin on these genes.
Girgert
Rainer
R
Department of Obstetrics and Gynecology, University of Göttingen, Göttingen, Germany.
Hanf
Volker
V
Emons
Günter
G
Gründker
Carsten
C
D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D044122:Receptor, Melatonin, MT1 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D044122:Receptor, Melatonin, MT1; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D008550:Melatonin