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 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 (2): p=0.06]). PEG-LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson (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. 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.