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: 7901389
• 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/7901389
• 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; 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（申请人提供）：尽管有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性，但我们目前对这些关系中涉及的机制的认识仍然不完整。我们的初步数据表明，特定的瘦素诱导的信号通路参与了乳腺肿瘤（MT）的同基因免疫活性小鼠模型中血管生成和有丝分裂相关因子水平的增加。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传导显著减少了MT的建立和生长，同时降低了VEGF/VEGFR 2的水平。在子宫内膜癌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，瘦素诱导的乳腺癌效应可能发生在瘦素信号激活Akt 1/NFkB和VEGF/VEGFR 2和bcl-2的表达增加后，这可能与IL-1信号相关或部分受IL-1信号调节。为了检验这一假设，将在体外和体内使用四种模型：（1）植入同基因免疫活性小鼠中的小鼠乳腺癌细胞;（2）植入免疫受损小鼠中的人乳腺癌细胞（对雌二醇有反应和无反应）;（3）用致癌剂（DMBA）处理的人乳腺上皮细胞;（4）在大鼠中诱导的DMBA-MT。将仔细检查瘦素水平在这些啮齿动物模型中MT的建立/进展中的影响。为了确定特异性瘦素诱导的信号传导途径的作用，将使用激酶抑制剂、siRNA、PEG化-LPrA（半衰期，55小时）。荧光素酶-VEGF启动子（小鼠和人）和几种转录因子-报告基因将用于研究瘦素在小鼠和人乳腺癌细胞中的靶点。IL-1 Ra对IL-1信号传导的抑制将用于确定瘦素/IL-1信号传导串扰对MT的影响。这项研究将扩大我们对瘦素/IL-1信号传导在MT中作用的有限知识，并可能为靶向乳腺癌的新治疗策略，特别是绝经后和肥胖妇女提供必要的数据。在这种情况下，抑制瘦素信号传导可以作为预防或辅助措施。