Neighborhood redlining, economic deprivation, and the breast tumor epigenome: bridging social and molecular epidemiology to address the Black-White breast cancer mortality disparity

项目摘要/摘要 意义重大。尽管国家和慈善机构的努力试图减少和消除乳腺癌 (BC)在过去的几十年里，死亡率差距不仅持续存在，而且还在扩大。另外， 我们对雌激素受体阳性(ER+)疾病的种族死亡率差异的了解有限， 尽管ER+肿瘤约占BC诊断的70%。驱动差异的一个潜在机制是更高的 黑人女性对内分泌治疗的从头抵抗率或获得性抵抗率，可能由以下因素引起 更高水平的心理社会应激、促炎细胞因子和核因子-kappaB的激活 (NF-κB)信号通路。歧视性政策(如红线)产生的社会压力有 能够在生物学上嵌入乳腺肿瘤的表观基因组，从而改变预后。这些 在社会和分子流行病学的交叉点上，以前从未探索过这种机制。 创新。我们的建议是创新的，因为它将是第一个将乳腺肿瘤表观基因组作为 将经济剥夺(源于住房歧视)与不良乳腺癌联系起来的机制 结果。接近。这项研究将利用佐治亚州癌症登记处来识别、招募和确定 被诊断为ER阳性的黑人和白人绝经后妇女的居住和经济史 第一阶段-第三阶段BC(2013-2017)在亚特兰大大都会区，并持续了长达12年。我们会估计这种联系 在地区一级的经济剥夺(目标1，N=4,433)、个人一级的经济剥夺(目标2， N~1,750)和BC结果通过种族探索潜在的异质性。我们将研究在多大程度上 个人层面的经济剥夺利用整个表观基因组分析扰乱DNA甲基组(目标3， N~750)。冲击力。这项研究的结果将突出持续结构的潜在机制 政府和金融机构的偏见会影响乳腺癌结果的差异。我们假设 持续的住房歧视导致了地区和个人层面的终身经济贫困-- 导致炎症和内分泌反应改变。建立BC的生物学背景 住房歧视引起的差异将为社会背景因素如何推动 不同地区和种族的癌症差异。这项研究最终将促进我们对这项政策的理解 促进健康公平所需的变化，同时将促进确定药理学或 个人层面的行为干预。

PROJECT SUMMARY/ABSTRACT Significance. Although national and philanthropic efforts have sought to reduce and eliminate breast cancer (BC) mortality disparities over the past few decades, they have not only persisted—but widened. Additionally, our knowledge about drivers of race mortality disparities in estrogen receptor–positive (ER+) disease are limited, despite ER+ tumors representing ~70% of BC diagnoses. One potential mechanism driving disparities is a higher rate of de novo or acquired resistance to endocrine therapy among Black women, which can be precipitated by higher levels of psychosocial stress, pro-inflammatory cytokines, and activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Social stressors emanating from discriminatory policies (such as redlining) have the capacity to become biologically embedded in the epigenome of the breast tumor, altering prognosis. These mechanisms, at the intersection of social and molecular epidemiology, have never before been explored. Innovation. Our proposal is innovative in that it will be the first to examine the breast tumor epigenome as a mechanism linking economic deprivation (stemming from housing discrimination) to adverse breast cancer outcomes. Approach. This study will leverage the Georgia Cancer Registry to identify, recruit, and ascertain residential and economic history from Black and White postmenopausal women diagnosed with ER-positive stage I–III BC (2013–2017) in metro-Atlanta and followed for up to 12 years. We will estimate the association between area-level economic deprivation (Aim 1, N=4,433), individual-level economic deprivation (Aim 2, n~1,750) and BC outcomes exploring potential heterogeneity by race. We will examine the extent to which individual-level economic deprivation perturbs the DNA methylome using whole epigenome analyses (Aim 3, n~750). Impact. The results of this study will highlight the potential mechanism by which persistent structural biases perpetrated by government and financial institutions impact breast cancer outcome disparities. We posit that persistent housing discrimination contributes to area- and individual-level economic deprivation over the life- course, resulting in altered inflammatory and endocrine response. Establishing a biological background for BC disparities stemming from housing discrimination will provide new insights into how socio-contextual factors drive cancer disparities by place and race. This research will ultimately advance our understanding of the policy changes needed to advance health equity and, in parallel, will facilitate the prioritization of pharmacologic or behavioral interventions at the individual level.