Abstract LB-365: Regulation of VEGFR-2 by leptin-Notch signaling crosstalk in mammary cancer cells

Abstract VEGFR-2 (Flk-1 or KDR) is generally recognized as the major form that mediates VEGF-induced response and the earliest marker for endothelial cell development. More importantly, VEGFR-2 directly regulates tumor angiogenesis and cancer cell survival through autocrine/paracrine mechanisms. We have previously reported that leptin signaling induced the growth of breast cancer mainly through the up-regulation of pro-angiogenic and pro-proliferative molecules, i.e., VEGF/VEGFR-2. Disruption of leptin signaling markedly reduced the growth of tumors and the expression of VEGFR-2 in mouse models of syngeneic and human breast cancer xenografts (ER+ and ER-). On the other hand, Notch signaling is essential for tumor angiogenesis. We hypothesized that a crosstalk between Notch and leptin signaling could impact the expression of VEGFR-2 in breast cancer. To test this hypothesis, the 5′-end transcription region of mouse VEGFR-2 gene was cloned and used to establish VEGFR2-Luc assays in mouse mammary tumor (MT) cells. Leptin induced VEGFR-2-Luc activity through JAK2, JNK, p38 MAP kinase, as well as PKC signaling pathways and up-regulated several members of Notch family (Notch 1∼4) in MT. Interestingly, leptin-induced VEGFR-2 transcriptional activity was significantly inhibited by a gamma-secretase inhibitor which blocks Notch pathway activation. These results suggest that leptin and Notch signaling crosstalk could impact on angiogenesis and growth of MT. Furthermore, VEGFR-2 transcription and expression was heavily depending on VEGFR-2 gene methylation and histone acetylation that could be linked to leptin's effects. Our results provide novel evidence on how VEGFR-2 could be regulated in breast cancer. Present data reinforce the idea that disruption of leptin signaling could reduce tumor angiogenesis/growth by inhibiting leptin-mediated up-regulation of VEGFR-2 and/or by negatively impacting on signals from some key members of Notch family. This might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis. [This work was supported in part by NIH/NCI 1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1; NIH/UAB Breast SPORE Career Development Award and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP)]. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-365.