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

瘦素和白细胞介素 1 信号转导参与乳腺癌进展

• 批准号: 7342275
• 负责人: Ruben Rene Gonzalez-Perez
• 金额: $ 28万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-29 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342275
• 关键词: Adjuvant; Apoptotic; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Cell Proliferation; Cells; Data; Development; Diet; Endometrial; Epithelial Cells; Estradiol; Funding; Government; Growth; Half-Life; Human; Immunocompetent; Immunocompromised Host; Implant; In Vitro; Incidence; Individual; Interleukin-1; Investigation; Knowledge; Laboratories; Leptin; Link; Luciferases; Mammary Neoplasms; Mammary gland; Measures; Mediating; Mitosis; Modeling; Mus; Neoplasm Metastasis; Obesity; Peptide Receptor; Phosphotransferases; Postmenopause; Prevention; Publishing; Rapid Access to Intervention Development; Rattus; Regulation; Relative (related person); Reporter; Research; Research Design; Rodent Model; Role; SP1 gene; Secure; Signal Pathway; Signal Transduction; Small Interfering RNA; System; Testing; Transcription Factor AP-1; Transcriptional Activation; Tumor-Derived; Up-Regulation; Vascular Endothelial Growth Factors; Woman; anakinra; angiogenesis; cancer cell; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; leptin receptor; malignant breast neoplasm; mouse model; novel therapeutics; promoter; transcription factor; tumor progression

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.

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机制的了解仍然不完整。我们的初步数据表明，在乳腺肿瘤（MT）的同基因免疫活性小鼠模型中，特定的瘦素诱导的信号通路参与了与血管生成和有丝分裂相关的因子水平的增加。我们的创新瘦素肽受体拮抗剂 (LPrA) 在体外和体内抑制瘦素信号传导，显着减少 MT 的建立和生长，同时降低 VEGF/VEGFR2 的水平。在子宫内膜癌细胞和乳腺癌细胞中发现的瘦素和 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。 据推测，瘦素诱导的对乳腺癌的作用可能发生在瘦素信号传导 Akt1/NFkB 激活以及 VEGF/VEGFR2 和 bcl-2 表达增加的情况下，这可能与 IL-1 信号传导相关或部分受到调节。为了验证这一假设，将在体外和体内使用四种模型：（1）将小鼠乳腺癌细胞植入同基因免疫活性小鼠体内； (2) 将人乳腺癌细胞（对雌二醇有反应和无反应）植入免疫受损的小鼠体内； (3)用致癌剂(DMBA)处理的人乳腺上皮细胞； (4)大鼠体内诱导DMBA-MT。将仔细检查瘦素水平对这些啮齿动物模型中 MT 建立/进展的影响。为了确定特定瘦素诱导的信号传导途径的效果，将使用激酶抑制剂、siRNA、聚乙二醇化-LPrAs（半衰期，55 小时）。荧光素酶-VEGF 启动子（小鼠和人类）和几种转录因子报告基因将用于研究小鼠和人类乳腺癌细胞中瘦素的靶标。 IL-1Ra 对 IL-1 信号传导的抑制将有助于确定瘦素/IL-1 信号传导串扰对 MT 的影响。这项研究将扩展我们对 MT 中瘦素/IL-1 信号传导作用的有限知识，并可为针对乳腺癌的新治疗策略（特别是针对绝经后和肥胖女性）提供重要数据。在这种情况下抑制瘦素信号传导可能作为预防或辅助措施。