P3-01-10: DMBA-Breast Cancer in Diet Induced Obesity (DIO) and Lean Mice Is Related to Leptin Signaling.
Authors: Gillespie C , Penichet MG , Colbert LS , McGlothen T , Guo S , Zhou W , Gonzalez-Perez RR 
Published: June 2012

Introduction: Leptin, the major adipokine released by adipose tissue, is strongly linked to obesity related-cancers. We have shown previously that inhibition of leptin signaling with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) negatively impacted human xenograft and syngeneic mouse breast cancer growth as well as VEGF/VEGFR2 levels [1,2].

Objective: We hypothesize that leptin signaling is essential for 7,12-dimethylbenz[A]anthracene (DMBA)-mammary tumor (MT) particularly in obese mice.

Methods: The study investigated the potential of PEG-LPrA2 to prevent MT 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 DIO-mice (95% obese mice after 5 weeks) with high fat diet (PDI-1; 45% Kcal from fat). Lean mice were fed a normal diet (PDI-1; 5% Kcal from fat). PEG-LPrA2 was administered intravenously. Lean and DIO-mice received either one or two PEG-LPrA2 dose/week (50 ml/0.1 mM) two weeks prior to DMBA to test its preventative potential through the end point (32 weeks). Control mice received saline injections.

Results: Obesity was positively correlated to the development of DMBA-MT in mice. MTs were found in 17% of lean control and 69% of DIO-control mice. Notably, 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-dose 0% MT). PEG-LPrA2 treatment did not alter body weight nor food intake in lean or DIO-mice. VEGF levels were significant higher (32 fold) in control DIO-mice. PEG-LPrA2 inhibition of leptin signaling decreased tumor levels of Notch ligands (Jagged-1 & DLL-4), receptors (Notch 1–4) and target genes (Survivin and Hey2) and reduced OB-R, IL-1R tI, VEGF/VEGFR2, bcl-2, HIF-1a and NFκB (p50 and p105).

Conclusions: Present data strongly suggest that leptin signaling is essential for DMBA-induced MT in the context of obesity. Overall, the effective chemoprevention of DMBA-MT by PEG-LPrA2 treatment in DIO and lean mice reinforces the potential use of leptin signaling inhibition for breast cancer prevention. These observations are most significant for obese populations showing higher levels of leptin and incidence of breast cancer. [This work was supported in part by NIH/NCI1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1 and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP); CREDO (MSCR) 2R25RR017694-06A1 to L.S.C; the Morehouse School of Medicine (MSM) MBRS RISE Program (NIH/NIGMS 506 GM08248) to T.Z.M; and facilities and support services at Morehouse School of Medicine (NIH RR03034 and 1C06 RR18386)].

References:

[1] Gonzalez RR, Chefils S, Escobar M, et al. Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 2006, 281(36): 26320–26328.

[2] Gonzalez RR, Watters A, Xu, Y, et al. Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res 2009, 11:R36.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-10.