Abstract
Abstract Leptin and its receptor, OB-R, are overexpressed in cancer cells and their levels correlate to worse prognosis of cancer patients. Leptin is an important inducer of VEGF/VEGFR2 in breast cancer under normoxia through the activation of several signaling pathways and HIF-1α/NFκB/SP1. However, the specific mechanisms of leptin-mediated regulation of VEGF/VEGFR2 genes are still partially unknown. VEGF/VEGFR2 directly regulates tumor angiogenesis and also works as an essential autocrine/paracrine process for cancer cell proliferation and survival. We have previously shown that disruption of leptin signaling with our novel antagonists, PEG-LPrAs, significantly impaired the growth of breast tumors and reduced the levels of VEGF/VEGFR2. We hypothesize that leptin regulation of VEGF/VEGFR2 in breast cancer involves the activation of Src and Gbr2/Gab2/STAT3 and crosstalk to Rho-GTPases. Methods: To test this hypothesis, VEGF/VEGFR2 expression and activation of signaling intermediaries were determined in mouse and human breast cancer cells challenged with leptin as well as genetic and pharmacologic kinase inhibitors. Results: Inhibition of JAK2 partially reduced leptin-induced pSTAT3 levels but increased VEGF protein and mRNA. Moreover, leptin-induced pSTAT3 was related to Src and Gab2. Inhibition of Src increased leptin-induced VEGF and dramatically reduced VEGFR2. Rac1 inhibition also abrogated leptin-induced pSTAT3 and decreased pGab2 and VEGF/VEGFR2 levels. Conclusions: Leptin activation of Rac1 upregulates VEGF/VEGFR2 and promotes a negative feed-back, which downregulates leptin activation of Src/Gbr2/Gab2/STAT3. In addition, leptin activation of Src/Gbr2/Gab2 and Rac1 are needed for the induction of VEGFR2. These data suggest a high complexity of signaling crosstalk is involved in leptin regulation of pro-angiogenic factors and breast cancer growth. Therefore, PEG-LPrA combined with inhibitors for leptin-sensitive regulatory signaling partners could provide novel multiple target therapies for breast cancer. This could be of paramount importance for the higher risk patients: obese and postmenopausal women who show highest leptin levels. Our proposed studies could also be relevant to patients having the very aggressive and difficult to treat triple negative breast cancer. 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 1009. doi:10.1158/1538-7445.AM2011-1009
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