title: Melatonin Represses Metastasis in Her2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression.
abstract: The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the antimetastatic actions of melatonin have not been well established. In the present study, the antimetastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition, and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.
  
  
  
  Melatonin inhibition of Rsk2 represses the metastatic phenotype in breast cancer cells suppressing EMT or inhibiting other mechanisms that promote metastasis; disruption of the melatonin signal may promote metastatic progression in breast cancer. Mol Cancer Res; 14(11); 1159-69. ©2016 AACR.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Whitney
authors.initials: W
authors.lastname: Summers
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Shulin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Amberly
authors.initials: A
authors.lastname: Reynolds
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wren-Dail
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: David
authors.initials: D
authors.lastname: Pointer
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Tripp
authors.initials: T
authors.lastname: Frasch
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana. smhill@tulane.edu.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008550:Melatonin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D008550:Melatonin; D018719:Erb-b2 Receptor Tyrosine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C508053:ERBB2 protein, human; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3