Abstract 4086: Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin regulation of VEGF/VEGFR-2 in breast cancer

Elevated levels of leptin and its deregulated signals have been strongly associated to obesity-related cancers, including breast cancer. Higher levels of leptin and leptin receptor, OB-R, are expressed by breast cancer cells, which commonly correlated with metastasis and lower survival of breast cancer patients. We have previously reported that leptin signaling induced the growth of breast cancer mainly through the up-regulation of pro-angiogenic molecules, i.e., VEGF/VEGFR-2, IL-1. Disruption of leptin signaling markedly reduced the growth of tumors and the expression of VEGF/VEGFR-2 in syngeneic and human breast cancer xenograft mouse models (ER+ and ER-). We speculate leptin interacts with Notch (essential for tumor progression and angiogenesis) in breast cancer cells through complex molecular mechanisms. We hypothesized that a crosstalk between leptin and Notch signaling could impact the expression of pro-angiogenic molecules in breast cancer. Methods: To test this hypothesis leptin-mediated activation of Notch signaling pathway (Notch1,3,4 NICD and CSL) and VEGF/VEGFR2 expression were determined in mouse (4T1, EMT6 and MMT) and human breast cancer cell lines (MCF-7 and MDA-MB-231) under normoxic conditions. Results: Leptin upregulates Notch receptors/ligands and also Notch-target genes, Hey2 and survivin in breast cancer cells. Notably, these leptin effects were more evident in triple negative breast cancer cells (MDA-MB231). Leptin-induction of CSL promoter activity was linked to multiple signaling pathways (MAPK, PI-3K/mTOR, PKC, p38 and JNK). Interestingly, leptin upregulatory effects on pro-angiogenic factors IL-1, VEGF/VEGFR-2 and Notch were significantly abrogated by a γ-secretase inhibitor, DAPT, as well as siRNA against CSL. In addition, IL-1 tI antibody inhibits leptin induced Notch, Notch target genes, Hey2 and survivin as well as VEGF/VEGFR-2 expression. Conclusions: These data suggest leptin-induced IL-1 signaling is related to leptin effects on Notch signaling. Our results further indicate that a novel unveiled crosstalk between Notch, IL-1 and leptin occurs in breast cancer. Indeed, leptin up-regulation of pro-angiogenic molecules: Notch, VEGF/VEGFR-2, IL-1 requires the activation of Notch signaling in breast cancer cells. Therefore, the integration of developmental, pro-inflammatory and pro-angiogenic signals (Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be critical for leptin regulation of VEGF/VEGFR-2 in breast cancer. This novel finding might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis, especially in triple negative breast cancer patients. [This work was supported in part by NIH/NCI1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1and the 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 4086. doi:10.1158/1538-7445.AM2011-4086