Inflammation Pathways in Breast Cancer

描述（由申请人提供）：65-79岁女性的乳腺癌占所有新诊断乳腺癌的50%以上，但已知的遗传和环境风险因素占风险的一小部分。大多数公认的、适度升高的老年妇女乳腺癌危险因素的病因学重要性可追溯到累积的雌激素暴露。老年妇女中其他适度升高的风险因素，如与肥胖、饮酒和缺乏体力活动有关的因素，可能通过刺激慢性激活的促炎免疫反应与乳腺癌有关，这种免疫反应具有直接的细胞毒性或遗传毒性。 方面的影响.我们将在老年女性（65-79岁）乳腺癌的完整研究的基础上，评估尼古丁驱动的炎症通路中的单一或多个多态性导致不平衡的免疫反应的可能性，这种免疫反应有利于不受控制的细胞增殖，随着时间的推移，乳腺癌。我们假设：1）有利于促炎反应的细胞因子基因变异与老年妇女乳腺癌风险增加相关，而有利于抗炎反应的细胞因子基因变异与风险降低相关。我们将评估促炎（IL 1、IL 6、IL 8、IL 12、TNF和瘦素）和抗炎（IL 1 RN、IL 2、IL 10、脂联素）基因及其受体的多态性是否改变乳腺癌的风险; 2）特定基因-基因和基因-环境组合的影响改变了乳腺癌的风险。 老年妇女患乳腺癌的风险（例如，配体-受体对，IL 6和瘦素，TNF和酒精）。由于细胞因子构成了介导炎症反应的基本布线，并且由于老年女性与指示低度全身炎症反应的年轻女性相比具有不同的细胞因子谱，我们提出细胞因子基因的变化是将老年女性常见的暴露转化为乳腺癌风险因素的关键因素，并可能为该年龄组的预防策略提供见解。最有可能患乳腺癌的女性概述：我们计划研究与细胞因子基因相关的绝经后乳腺癌的风险，细胞因子基因是低度慢性炎症反应的基础。与年轻女性相比，老年女性中细胞因子基因的表达水平不同;因此，我们还将通过肥胖和HRT使用等常见暴露水平来评估其对乳腺癌风险的贡献。

DESCRIPTION (provided by applicant): Breast cancers in women 65-79 years old comprise over 50% of all newly diagnosed breast cancers, and yet known genetic and environmental risk factors account for a small percentage of risk. The majority of the recognized, modestly elevated risk factors for breast cancer in older women trace their etiologic importance to cumulative estrogen exposure. Other modestly elevated risk factors in older women, such as those associated with obesity, alcohol use, and physical inactivity, may be linked to breast cancer through stimulation of a chronically activated proinflammatory immune response that has direct cytotoxic or genotoxic effects. We will build on a completed study of breast cancer in older women (ages 65-79) to assess the possibility that single or multiple polymorphisms in the cytokine-driven inflammation pathways lead to an unbalanced immune response that favors uncontrolled cell proliferation and, over time, breast cancer. We hypothesize that 1) Variation in cytokine genes that favor a proinflammatory response are associated with an increased risk of breast cancer in older women, whereas those that favor an anti-inflammatory response are associated with a decreased risk. We will evaluate whether polymorphisms in proinflammatory (IL1, IL6, IL8, IL12, TNF, and leptin) and anti- flammatory (IL1RN, IL2, IL10, adiponectin) genes and their receptors alter the risk of breast cancer; 2) The impact of specific gene-gene and gene-environment combinations alter the risk of breast cancer in older women (e.g., ligand-receptor pairs, IL6 and leptin, TNF and alcohol). As cytokines constitute the basic wiring that mediates the inflammatory response and since older women have different cytokine profiles compared to younger women that indicate a low-grade systemic inflammatory response, we propose that variation in cytokine genes are key players in translating exposures common in older women to risk factors for breast cancer and may provide insight into strategies for prevention in this age group, the women who are most at risk for breast cancer. Lay Summary: We plan to study the risk of postmenopausal breast cancer associated with cytokine genes that underlie a low-grade, chronic inflammatory response. Cytokine genes are expressed at different levels in older compared to younger women; therefore, we will also evaluate their contribution to breast cancer risk by levels of common exposures such as obesity and HRT use.