title: Obesity induced a leptin-Notch signaling axis in breast cancer.
abstract: To investigate whether obesity induces a leptin-Notch signaling axis in breast cancer (BC), leptin-induced Notch was determined in human MCF-7 and MDA-MB231 and mouse E0771 cells and in E0771-BC hosted by syngeneic lean and diet-induced obesity (DIO) C57BL/6J female mice. Lean and DIO mice were treated for 3 weeks with leptin inhibitor (PEG-LPrA2) 1 week after the inoculation of E0771 cells. Leptin induced Notch1, 3 and 4 in BC cells, but Notch2 expression showed opposite pattern in MCF-7 compared to MDA-MB231 cells. Notch loss-of-function (DAPT and dominant negative [R218H] RBP-Jk [CSL/CBF1]) showed that a functional leptin-Notch signaling axis was involved in the proliferation and migration of E0771 cells. E0771-BC onset was affected by obesity (lean mice7/10 [70%] vs. DIO mice: 11/12 [92%]; Pearson χ(2) : p = 0.06]). PEG-LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson χ(2) : p = 0.008). PEG-LPrA2 did not influence the caloric intake of mice but increased carcass and/or body weights of lean and DIO mice inoculated with E0771 cells, which could be related to the improvement of health conditions (less aggressive disease). Importantly, BC from obese mice had higher levels of Notch3, JAG1 and survivin than lean mice. Inhibition of leptin signaling reduced protein levels of Notch (NICD1, NICD4, Notch3, JAG1 and survivin) and significantly decreased mRNA expression of Notch receptors, ligands and targets. PEG-LPrA's effects were more prominent in DIO mice. Present data suggest that leptin induces Notch, which could be involved in the reported higher incidence and aggressiveness and, poor prognosis of BC in obese patients.
authors.affiliation: Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA.
authors.forename: Monica
authors.initials: M
authors.lastname: Battle
authors.forename: Corey
authors.initials: C
authors.lastname: Gillespie
authors.forename: Alexander
authors.initials: A
authors.lastname: Quarshie
authors.forename: Viola
authors.initials: V
authors.lastname: Lanier
authors.forename: Tia
authors.initials: T
authors.lastname: Harmon
authors.forename: Kaamilah
authors.initials: K
authors.lastname: Wilson
authors.forename: Marta
authors.initials: M
authors.lastname: Torroella-Kouri
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Gonzalez-Perez
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D020738:Leptin / Q000097:blood* / Q000235:genetics; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood* / Q000235:genetics / Q000473:pathology; D051880:Receptors, Notch / Q000097:blood* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D002135:Calcium-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D020738:Leptin; D008565:Membrane Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D000077022:Survivin
keywords: E0771 cells; PEG-LPrA2; breast cancer, obesity, leptin, notch; dominant negative RBP-Jk; high-fat diet