Breast White Adipose Tissue Inflammation and Breast Cancer Outcomes

摘要 诊断为乳腺癌时的肥胖和过度肥胖与 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预后的策略提供关键的见解。 我们在乳房脂肪组织中发现了一种新的组织炎性生物标志物--冠状结构 乳房(CLS-B)，我们已经证明与肥胖和代谢失调因素有关。 CLS-B由脂肪细胞组成，周围环绕着一顶巨噬细胞， 表示乳房白色脂肪组织处于炎症状态(B-Wati)。我们之前报道过B- WATI与代谢综合征的特征有关。重要的是，B-Wati与 在患有转移性疾病的女性中，乳腺癌风险和复发时间缩短。 路径研究是一项对浸润性乳腺癌妇女的前瞻性队列研究，由 NCI癌症流行病学队列基础设施赠款，提供了一个开展大型- 量表，与B-Wati相关的病理生理状态的权威性调查，并调查 B-Wati与乳腺癌预后的关系。从2006年1月到2013年5月，我们招收了一名种族- 以及在Kaiser Permanente被诊断出乳腺癌后不久的4505名不同种族的女性队列 北加州(KPNC)。路径研究参与者提供了血液样本并报告了生活方式 因素，包括饮食和体力活动。链接到KPNC电子健康记录可获取以下详细信息 癌症诊断和临床护理，以及诊断玻片和福尔马林固定的石蜡-生物库- 嵌入的组织块是从所有队列成员的最终乳腺癌手术中创建的。 我们建议确定路径研究参与者中B-Wati的存在和严重程度 乳房切除术(n=1,982)，利用生物信息库中可用的大量非肿瘤乳腺组织。我们 还建议检测炎症和代谢异常的系统性措施，并检查 用计算机断层扫描(CT)图像研究一组女性的脂肪组织分布。具体目标是 1)研究浸润性乳腺癌患者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特征的关系；2) 确定B-Wati和乳腺癌预后之间的关联；以及，3)检查 B-Wati与乳腺癌预后的关系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、疾病阶段和乳腺癌 治疗。该项目将B-Wati的开创性和创新性工作与杰出的 路径研究的资源和基础设施。它承诺提供对B-Wati影响的洞察 对乳腺癌的影响，并确定可采取行动和可改变的风险因素，以改善乳腺癌的预后。

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.