Obesity induced a leptin‐Notch signaling axis in breast cancer

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 trea...

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Bibliographic Details
Published in:International journal of cancer 2014-04, Vol.134 (7), p.1605-1616
Main Authors: Battle, Monica, Gillespie, Corey, Quarshie, Alexander, Lanier, Viola, Harmon, Tia, Wilson, Kaamilah, Torroella‐Kouri, Marta, Gonzalez‐Perez, Ruben R.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Body Weight - physiology
Breast cancer
breast cancer, obesity, leptin, notch
Breast Neoplasms - blood
Breast Neoplasms - genetics
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Cancer
Cell Growth Processes - physiology
Cell Line, Tumor
Cell Movement - physiology
dominant negative RBP‐Jk
E0771 cells
Female
high‐fat diet
Hormones
Humans
Inhibitor of Apoptosis Proteins - genetics
Inhibitor of Apoptosis Proteins - metabolism
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Jagged-1 Protein
Leptin - blood
Leptin - genetics
MCF-7 Cells
Medical research
Medical sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metabolic diseases
Mice
Mice, Inbred C57BL
Mice, Obese
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Obesity
Obesity - blood
Obesity - genetics
Obesity - pathology
PEG‐LPrA2
Receptors, Notch - blood
Receptors, Notch - genetics
Repressor Proteins - genetics
Repressor Proteins - metabolism
Risk factors
Rodents
Serrate-Jagged Proteins
Signal Transduction
Tumors
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Summary: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 χ2: p = 0.06]). PEG‐LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson χ2: 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. What's new? Obesity is known to increase the risk of several types of cancer, including breast cancer (BC). The molecular mechanisms are not well understood, however. In our study, the authors found that the hormone leptin, which is elevated in obesity, may be linked to an increase in Notch signaling. Notch expression in BC is associated with angiogenesis, proliferation, more aggressive tumors and poor prognosis. Targeting the leptin‐Notch axis may therefore provide valuable therapeutic and preventive strategies in BC, which would be especially relevant for obese patients at risk.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.28496