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Environmental carcinogens, High-Fat Diet (HFD) and elevated levels of leptin correlate to increase breast cancer incidence. To test whether these factors could affect the development of Mammary Tumors (MT) via DMBA (7,12-dimethylbenz[a]anthracene) challenge, we used C57BL/6J mice that are non-responsive to develop MT in absence of hormonal stimulation. C57BL/6J female mice without hormonal stimulation were fed HFD (55% Kcalfat) and low-fat diets (10% Kcal-fat) received DMBA (oral gavage: 1 mg/weekly) for 6 weeks. To test whether leptin signaling is involved in DMBA-MT development, a potent inhibitor, pegylated leptin peptide receptor antagonist (PEG-LPrA2; half-life 66 hours), was used for 30 weeks. As expected, irrespective of PEG-LPrA2 treatment, lean mice fed with low-fat diet did not develop MT. However, HFD induced obesity and significantly stimulated earlier onset (within 18 weeks) and marginally increased the incidence of MT (21%; 3/14) in DIO-mice (diet-induced-obesity). It appears that leptin signaling may be involved in DMBA-induced mammary carcinogenesis in obese mice because no evidence of MT was found in DIO-mice treated with PEG-LPrA2 (0% incidence; 0/14; Wilcoxon-Breslow test Chi2, p=0.03). Interestingly, PEG-LPrA2 treatment did not apparently affect body weight or food intake, but reduced protein levels of several molecules related to breast cancer [Aryl hydrocarbon Receptor (AhR), leptin receptor (OBR), interleukin 1 receptor type I (IL-1R tI), hypoxia-induced factor 1 alpha (HIF-1α), Jagged1 (JAG1) and Notch1 activated (NICD1)] within the mammary glands. Our findings reinforce the idea that obesity induced by HFD is an additional risk factor for chemical-induced breast carcinogenesis. The present study reveals some potential mechanisms involving leptin in the effects of HFD and adiposity on mammary chemical-induced carcinogenesis. Overall, present data suggest that the inhibition of leptin signaling might be a new way to prevent breast cancer induced by chemical carcinogens, especially in obese individuals.

Potential Role of Leptin Signaling in DMBA induced Mammary Tumors by Non-Responsive C57BL/6J Mice Fed a High-Fat Diet