Obesity, inflammation and breast cancer

 描述（由申请人提供）：乳腺癌是最常见的癌症类型（约1，383，500例新发病例/年），是全球女性癌症相关死亡的主要原因（约458，400例死亡/年），也是美国第二大致死性癌症。肥胖发生在美国36%的成年人中，导致乳腺癌的发病率和进展。尽管几种炎性细胞因子与乳腺癌有关，但它们在肥胖驱动的癌症进展中的独特作用在很大程度上是难以捉摸的。我们的初步数据确定了白细胞介素-1 β（IL-1 β）/IL-1 R1信号级联反应是不同肿瘤模型中肥胖驱动的乳腺癌进展（ODBP）所必需的。我们的长期目标是了解ODBP的机制，并预防或治疗肥胖乳腺癌患者。所提出的研究的目的是确定NLRC 4-炎性体和IL-1/IL-1 R1轴如何在肥胖条件下驱动乳腺癌进展的机制。我们的中心假设是，来自肥胖肿瘤的一些危险信号诱导NLRC 4-炎性小体活化和随后的肿瘤相关基质中的IL-1β产生，这反过来又通过诱导血管生成促进肿瘤进展。因此，我们提出了以下具体目标：具体目标1：确定NLRC 4-炎性体在ODBP中的相关性。具体目标二：确定NLRC 4如何促进肿瘤微环境中的ODBP;具体目标3：探索治疗肥胖乳腺癌患者的新的联合方案。我们的研究结果有望对指导靶向治疗以抑制肥胖患者乳腺癌进展产生积极影响。现有药物的潜在应用，如阿那白滞素（已知对治疗其他疾病安全有效）或一些用于乳腺癌治疗的长效Casp-1抑制剂，将大大缩短药物开发过程。这项研究可能会使超过三分之一的乳腺癌患者受益，因为在美国约有36%的成年人肥胖。

 DESCRIPTION (provided by applicant): Breast cancer is the most prevalent cancer type (~1,383,500 new cases/year), the leading cause of cancer-associated death among woman worldwide (~458,400 death/year), and the 2nd most lethal cancer in the United States. Obesity happens in 36% adults in the United States, contributing to breast-cancer incidence and progression. Whereas several inflammatory cytokines are implicated in breast cancer, their distinct roles in obesity-driven cancer progression are largely elusive. Our preliminary data identified interleukin-1 (IL-1)/IL-1R1 signaling cascade to be required for obesity-driven breast cancer progression (ODBP) from different tumor models. Our long-term goal is to understand the mechanisms that underlie ODBP, and to prevent or treat obese breast-cancer patients. The objective of the proposed research is to determine the mechanism how NLRC4-inflammasome and IL-l/IL-1R1 axis drive breast-cancer progression under obese condition. Our central hypothesis is that some danger signal from obese tumors induces NLRC4-inflammasome activation and subsequent IL-1β production in tumor-associated stroma, which in turn promotes tumor progression through the induction of angiogenesis. We thus propose the following specific aims: Specific Aim 1: Determine the relevance of NLRC4-inflammasome in ODBP. Specific Aim 2: Determine how NLRC4 promotes ODBP within the tumor microenvironment; Specific Aim 3: Explore novel combinatory regimens to treat obese breast-cancer patients. Our results are expected to have a positive impact on guiding targeted therapy for inhibiting the breast-cancer progression in obese patients. The potential application of available agents, such as anakinra (known to be safe and effective for the treatment of other diseases) or some long-lasting Casp-1 inhibitors for breast-cancer therapy, would significantly shorten the drug development process. The study may potentially benefit the over one third of breast-cancer patients considering that ~36% adults are obese in the United States.