Breast White Adipose Tissue Inflammation and Breast Cancer Outcomes

摘要 乳腺癌诊断时的肥胖和过度肥胖与乳腺癌发病率增加有关。 复发和癌症相关死亡的可能性。了解过度肥胖的机制 影响乳腺癌进展将为改善患者结局的策略提供重要见解。 我们在乳腺脂肪组织中发现了一种新的基于组织的炎症生物标志物，冠状结构 乳腺癌（CLS-B），我们已经证明与肥胖和失调的代谢因素。 CLS-B由巨噬细胞“冠”包围的脂肪细胞组成， 表示乳房白色脂肪组织（B-WATI）中的炎症状态。我们之前报道过B- WATI与代谢综合征特征相关。重要的是，B-WATI与增加的 乳腺癌的风险和缩短的时间复发转移性疾病的妇女。 Pathways研究是一项由一项研究支持的浸润性乳腺癌女性前瞻性队列研究， NCI癌症流行病学队列基础设施补助金，提供了一个很好的机会，进行一个大的- 量表，与B-WATI相关的病理生理状态的确定性研究，并研究 B-WATI与乳腺癌预后的关系。从2006年1月到2013年5月，我们招募了一名种族- 在Kaiser Permanente诊断乳腺癌后不久， 北方加州（KPNC）。路径研究参与者提供血液标本并报告生活方式 因素，包括饮食和身体活动。与KPNC电子健康记录的链接可获取以下详细信息 癌症诊断和临床护理，以及诊断载玻片和福尔马林固定的石蜡生物储存库， 已从所有群组成员的确定性乳腺癌手术中创建了包埋的组织块。 我们建议确定在接受过B-WATI治疗的路径研究参与者中B-WATI的存在和严重程度。 乳房切除术（n= 1，982），利用生物库中大量的非肿瘤乳房组织。我们 还建议分析炎症和代谢异常的系统性措施，并检查 脂肪组织分布在一个子集的妇女与计算机断层扫描（CT）图像。具体的目标是 目的：1）描述浸润性乳腺癌女性中B-WATI的病理生理状态，包括 与生活方式因素、脂肪组织分布、循环细胞因子和代谢谱的相关性; 2） 确定B-WATI和乳腺癌结果之间的关联;以及，3）检查 B-WATI和乳腺癌结果之间的关联因生活方式因素和其他乳腺癌而异 预后因素，如种族/民族、激素受体状态、疾病分期和乳腺癌 治疗该项目汇集了B-WATI的开创性和创新性工作， 路径研究的资源和基础设施。它承诺提供深入了解B-WATI的影响 并确定可采取行动和可改变的风险因素，以改善乳腺癌的结果。

ABSTRACT Obesity and excess adiposity at the time of breast cancer diagnosis are associated with increased likelihood of recurrence and cancer-related death. Understanding the mechanisms by which excess adiposity affects breast cancer progression would provide critical insights into strategies to improve patient outcomes. We have identified a novel tissue-based inflammatory biomarker in breast adipose tissue, crown-like structures of the breast (CLS-B), that we have shown to be associated with obesity and dysregulated metabolic factors. The presence of CLS-B, which are comprised of an adipocyte surrounded by a “crown” of macrophages, indicates a state of inflammation in the breast white adipose tissue (B-WATi). We previously reported that B- WATi is associated with metabolic syndrome characteristics. Importantly, B-WATi is associated with increased breast cancer risk and shortened time to recurrence in women with metastatic disease. The Pathways Study, a prospective cohort study of women with invasive breast cancer supported by an NCI cancer epidemiology cohort infrastructure grant, provides an outstanding opportunity to conduct a large- scale, definitive investigation of the pathophysiologic state associated with B-WATi, and to investigate the association of B-WATi with breast cancer outcomes. From January 2006 to May 2013, we enrolled a racially- and ethnically-diverse cohort of 4,505 women soon after a breast cancer diagnosis in Kaiser Permanente Northern California (KPNC). Pathways Study participants provided blood specimens and reported on lifestyle factors, including diet and physical activity. Linkage to KPNC electronic health records captures details of cancer diagnosis and clinical care, and a biorepository of diagnostic slides and formalin-fixed, paraffin- embedded tissue blocks has been created from definitive breast cancer surgeries for all cohort members. We propose to determine B-WATi presence and severity in Pathways Study participants who underwent mastectomy (n=1,982), leveraging the substantial non-tumor breast tissue available in the biorepository. We also propose to assay systemic measures of inflammation and metabolic aberration, and examine measures of adipose tissue distribution in a subset of women with computed tomography (CT) images. Specific Aims are to: 1) Characterize the pathophysiological state of B-WATi in women with invasive breast cancer, including associations with lifestyle factors, adipose tissue distribution, and circulating cytokine and metabolic profiles; 2) Determine the associations between B-WATi and breast cancer outcomes; and, 3) Examine whether the associations between B-WATi and breast cancer outcomes vary by lifestyle factors and other breast cancer prognostic factors such as race/ethnicity, hormone receptor status, stage of disease, and breast cancer treatment. This project brings together ground-breaking and innovative work on B-WATi with the outstanding resources and infrastructure of the Pathways Study. It promises to provide insight into the impact of B-WATi on breast cancer and to identify actionable and modifiable risk factors to improve breast cancer outcomes.