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 three weeks with leptin inhibitor (PEG-LPrA2) one 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 mice: 7/10 (70%) vs DIO-mice: 11/12 (92%); Pearson Chi2: P=0.06]. PEG-LPrA2 significantly reduced BC growth [untreated: 19/42; (45%) vs treated: 8/42 (19%); Pearson Chi2: 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, JAG-1 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.

Leptin signaling and cancer chemoresistance: Perspectives

“…Leptin induces RBP-Jk and Notch that impacts on CSC and self-renewal[16,60,71]. Moreover, a novel crosstalk between Notch, IL-1 and leptin (NILCO) was found in breast cancer[53,60,72]. NILCO induces proliferation/migration and upregulation of VEGF/VEGFR-2, and could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin effects in breast cancer[60].…”

“…LPrA1 and LPrA2 were earlier designed and tested in vitro and in vivo in mouse models[52,53,56,72,175,176]. LPrAs are composed by aminoacid sections of the binding site I (LPrA1) and III (LPrA2) of the leptin molecule[63].…”

“…LPrA2 was conjugate to polyethylene glycol 20 kDa (PEG-LPrA2) or to iron-oxide nanoparticles (IONP-LPrA2) to increase its bioavaibility and effectiveness to block leptin signaling in cancer cells. Unconjugated and conjugated LPrA2 effectively inhibited leptin-induced protumorigenic actions in breast and pancreatic cancer cells[52,53,56,72,175,176]. LPrA2 showed potent effects for the reduction of leptin-induced growth of tumors and expression of inflammatory (IL-1/IL-1R tI), proliferation (Ki67, PCNA), angiogenic factors (VEGF/VEGFR2) and Notch in tumors and endothelial cells[53,56,58,72].…”

“…Unconjugated and conjugated LPrA2 effectively inhibited leptin-induced protumorigenic actions in breast and pancreatic cancer cells[52,53,56,72,175,176]. LPrA2 showed potent effects for the reduction of leptin-induced growth of tumors and expression of inflammatory (IL-1/IL-1R tI), proliferation (Ki67, PCNA), angiogenic factors (VEGF/VEGFR2) and Notch in tumors and endothelial cells[53,56,58,72]. The antagonist effects of LPrA2 on tumor growth and angiogenesis were more evident in obese than in lean mice[53,72].…”

NILCO biomarkers in breast cancer from Chinese patients

“…Moreover, a functional Notch-leptin axis is found in mouse carcinogenic-induced [18] and syngeneic breast cancer [19]. In these mouse models, leptin signaling induces both the expression and activation of Notch.…”