Abstract 1400: Obesity induced leptin-notch signaling axis in breast cancer.

Abstract

Abstract Obesity leads to increased leptin levels and signaling which has been linked to the growth of breast cancer (BC). We early identified leptin as an inducer of Notch in BC cells. However, whether leptin-induction of Notch is instrumental to the development of BC is unknown. Objective: Therefore, we examined the impact of obesity and inhibition of leptin signaling (via LPrA2 antagonist) on the growth of syngeneic E0771-derived BC and tumor expression of Notch in lean and obese mice and in E0771 cell cultures. Methods: C57BL/6J female mice were fed either high-fat diet (HFD, 60% Kcal from fat) or normal diet (10% Kcal from fat). Obesity was defined as BW ≥ 20% BW Lean-control at week 5. Lean and diet-induced-obesity (DIO) mice were orthotopically inoculated with mouse E0771 cells in the lower left region of the mammary pad. One week later the mice were treated with either (1) pegylated leptin peptide receptor antagonist 2, PEG-LPrA2 or (2) PEG-Scrambled peptide (as control; 50μl i.v. tail vein/ 0.1 mM) following the two-arm design: (a) one and (b) two doses/weekly. Treatment lasted for 4 weeks. Tumor onset and growth was determined overtime and expression of Notch, its ligands, and crosstalk factors were assessed using western blot, immunohistochemistry, and ELISA. Leptin's effects on Notch and crosstalk factors were also investigated in E0771 cell cultures. Results: Obesity induced E0771-BC onset and growth and, increased the expression of Notch in vivo. Inhibition of leptin signaling had a higher impact on DIO mice than in lean mice by delaying onset and reducing tumor growth and the expression of Notch. Therefore, high levels of leptin in DIO-mice played a positive role in tumorigenesis. Similarly, leptin induced and PEG-LPrA2 decreased Notch expression in E0771 cells in vitro. Present data further validate the idea that the consumption of a high-fat diet leads to early BC onset and growth, which was linked to the leptin-Notch axis. Our results reinforce the potential use of inhibition of leptin signaling as a novel approach to fight breast cancer, especially in obese patients showing higher levels of leptin and incidence of BC. Funding: This work was supported by NIH/NCI 5SC1CA138658-03 and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP), NIH/2G12RR003034-26; U54 MSM/TU/UAB Cancer Center Partnership; and 1R21CA153172-01A1 (to MTK). This research was also supported, in part, facilities and support services at Morehouse School of Medicine (NIH 1C06 RR18386). Citation Format: Monica Battle, Corey Gillespie, Tanisha McGlothen, Marta Torroella-Kouri, Ruben R. Gonzalez-Perez. Obesity induced leptin-notch signaling axis in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1400. doi:10.1158/1538-7445.AM2013-1400