Involvement of Leptin and Interleukin-1 Signaling in Mammary Cancer Progression

描述（由申请人提供）：尽管越来越多的证据表明瘦素水平、肥胖、绝经后和乳腺癌发病率之间存在正相关，但我们目前对这些关系所涉及的机制的了解仍然不完整。我们的初步数据表明，特异性瘦素诱导的信号通路参与了同基因免疫能力小鼠乳腺肿瘤（MT）模型中血管生成和有丝分裂相关因子水平的升高。我们创新的瘦素肽受体拮抗剂（LPrA）在体外和体内抑制瘦素信号，显著减少MT的建立和生长，同时降低VEGF/VEGFR2的水平。在子宫内膜和乳腺癌细胞中发现瘦素和IL-1信号之间的特异性串扰可能参与其促血管生成和抗凋亡作用。

DESCRIPTION (provided by applicant): Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Our preliminary data show that specific leptin-induced signaling pathways are involved in the increased levels of factors related to angiogenesis and mitosis in syngeneic immuno-competent mouse models of mammary tumors (MT). The inhibition of leptin signaling in vitro and in vivo by our innovative leptin peptide receptor antagonists (LPrA) significantly reduced establishment and growth of MT and simultaneously decreased the levels of VEGF/VEGFR2. Specific cross-talk between leptin and IL-1 signaling found in endometrial and mammary cancer cells could be involved in their pro-angiogenic and anti-apoptotic effects. It is hypothesized that the leptin-induced effects on mammary cancer could occur upon leptin signaling the activation of Akt1/NFkB and an increased expression of VEGF/VEGFR2 and bcl-2, which may be linked to, or regulated, in part by IL-1 signaling. To test this hypothesis four models will be used in vitro and in vivo: (1) mouse mammary cancer cells implanted in syngeneic immuno-competent mice; (2) human breast cancer cells (responsive and irresponsive to estradiol) implanted in immuno-compromised mice; (3) human mammary epithelial cells treated with a carcinogenic agent (DMBA); (4) DMBA-MT induced in rats. The impact of leptin levels in establishment/ progression of MT in these rodent models will carefully be examined. To determine the effects of specific leptin-induced signaling pathways, kinase inhibitors, siRNAs, PEGylated-LPrAs (half-lives, 55h) will be used. Luciferase-VEGF promoter (mouse and human) and several transcription factor-reporters will be used to investigate leptin's targets in mouse and human mammary cancer cells. IL-1Ra inhibition of IL-1 signaling will serve to determine the impact of leptin/IL-1 signaling crosstalk on MT. This research would expand our limited knowledge on leptin/IL-1 signaling roles in MT and could generate essential data for new therapeutic strategies to target breast cancer, particularly for post-menopausal and obese women. Inhibition of leptin signaling in such instances might serve as a preventative or adjuvant measure.