Abstract 5297: Autocrine stimulation of VEGFR-2 by leptin is associated with Notch signaling pathway and cancer stem cell marker expression

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Obesity-related cancer is an increasing health problem. Leptin, the major adipokine, has been suggested a major factor in these relationships. Leptin is a pro-inflammatory, pro-angiogenic and mitogenic factor for breast cancer cells. Recently, we described a comprehensive mechanism for leptin induction of VEGF, and unveiled a novel crosstalk between Notch, IL-1 and leptin (NILCO) in breast cancer. NILCO regulates VEGF/VEGR-2 in breast cancer cells and could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin oncogenic actions. However, the specific mechanisms for leptin-induced VEGFR2 are unknown. To answer this question, we re-cloned mouse VEGFR-2 promoter and prepared VEGFR-2 luc, then analyzed VEGFR-2 regulation and expression by using several kinase inhibitors, leptin peptide antagonist 2 (LPrA2), a VEGFR-2 kinase inhibitor (SU5416), as well as siRNA against VEGFR-2, Notch1, Notch3 in 4T1 cells. Our results demonstrated that leptin-induced JAK2/STAT3, MAPK/ERK 1/2, PI-3K/AKT1, PKC, p38 and JNK signaling pathways may correlate with upregulated VEGFR-2. Moreover, leptin-induced activation of Notch/VEGFR-2 was linked to the upregulation of cancer stem cell markers CD44 and ALDH1. These leptin effects were inhibited by siRNA-Notch1&3, leptin signaling antagonist (PEG-LPrA2), VEGFR2-kinase inhibitor (SU5416) and siRNA-VEGFR-2. Our results show for the first time how leptin's molecular signals regulate VEGFR-2 (an autocrine survival process) that was associated to Notch and cancer stem cell marker expression. These novel findings may help to design new strategies for prevention/treatment of breast cancer through the abrogation of tumor angiogenesis and breast cancer stem cell renewal in an obesity context. [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)]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5297. doi:1538-7445.AM2012-5297