Abstract 825: Leptin signaling disruption prevents DMBA-induced mammary tumors in lean and diet-induced-obesity (DIO) mice
Authors: Corey Gillespie, Shanchun Guo, Weiqiang Zhou, Ruben Rene Gonzalez-Perez
Journal: Cancer Research (2011)

Abstract Leptin and its receptor (OB-R) are overexpressed in breast cancer tissues and their signals induce the expression of pro-angiogenic, pro-proliferation and pro-inflammatory factors and growth of breast cancer. We have previously shown that inhibition of leptin signaling with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) negatively impacted on the growth of mouse syngeneic and human breast cancer xenografts hosted by SCID mice. PEG-LPrA2 effects paralleled a significant reduction of VEGF/VEGFR2 levels. It is known that higher body weight is associated with increased incidence of spontaneous and chemically induced mammary tumors (MT) in rodents. However, leptin involvement in 7,12-dimethylbenz[a]anthracene (DMBA)-MT is unknown. Methods: In the present paper, we investigated the potential of PEG-LPrA2 to prevent MT development in lean and diet-induced-obesity (DIO)-C57BL/6J female mice treated with 1 mg/dose/weekly for 6 weeks of DMBA. Obesity was induced by feeding the DIO-mice (95% obese mice after 5 weeks) with a high fat diet (PDI-1; 45% Kcal from fat). Lean mice were fed with a normal diet (PDI-1; 5% Kcal from fat). DMBA challenge was initiated two weeks after PEG-LPrA2 treatment. Lean and DIO-mice were allocated (week 7 of study) into two chemoprevention treatment subgroups receiving either one or two PEG-LPrA2 dose/weekly (i.v.; 50 μl/0.1 mM) for 32 weeks. Lean and DIO-control mice received saline injections. Results: Obesity was positively correlated to the development of DMBA-MT in mice. DMBA-MT were found in 17% of lean control and 69% of DIO-control mice. Remarkably, PEG-LPrA2 prevented the onset of DMBA-MT in lean (one and two doses: 0% tumor-bearing mice) and DIO-mice (one dose, 29% and two doses 0% tumor-bearing mice). PEG-LPrA2 treatment did not change body weight or food intake in lean or DIO-mice. Strikingly, the expression of VEGF in DMBA-MT from DIO-control mice was significantly higher (32 fold) than in DIO-mice treated with PEG-LPrA2. Inhibition of leptin signaling decreased tumor levels of Notch ligands, receptors and activated NICD together with Notch targeted genes: survivin and Hey2. Moreover, PEG-LPrA2 treatment reduced the levels of several leptin-induced molecules within DMBA-MT: OB-R, IL-1R tI, VEGF/VEGFR2, bcl-2, HIF-1α and NFκB (p50 and p105). Conclusions: Obesity is an acceleration factor for DMBA tumorigenesis. Leptin signaling is essential for DMBA-induced MT. The effective chemoprevention of DMBA-MT by PEG-LPrA2 treatment in lean and, particularly, in DIO-mice reinforces the potential use of leptin signaling inhibition for breast cancer prevention. These observations are relevant, especially for obese populations showing higher levels of leptin and incidence of breast cancer. [Funding: NIH/NCI1SC1CA138658-02; ARRA/3SC1CA138658-02S1 and Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP)]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 825. doi:10.1158/1538-7445.AM2011-825