Molecular Determinants of Health Disparities in Inflammatory Breast Cancer

炎症性乳腺癌健康差异的分子决定因素

• 批准号: 10491148
• 负责人: Gayathri Devi
• 金额: $ 47.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491148
• 关键词: Address; Affect; African American; African ancestry; Age; Apoptosis; Apoptotic; Biological; Biological Assay; Biological Markers; Biology; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Breast Epithelial Cells; Breast Feeding; Breast biopsy; Cancer Biology; Cell Communication; Cell Death; Cell Line; Cessation of life; Characteristics; Chronic; Clinical; Clonal Evolution; Coculture Techniques; Communities; DNA Damage; Data; Data Set; Diagnosis; Disease; Disease Resistance; Drug resistance; Embolism; Epidemiology; Epigenetic Process; Ethnic Origin; Exhibits; Exposure to; Gene Expression; Genes; Genomic Instability; Growth; Health Services Accessibility; Homeostasis; Hormone Receptor; Immunohistochemistry; Implant; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; International; Lead; Lesion; Life; Link; Mammary Gland Parenchyma; Mammary gland; Maps; Mediating; Medical; Modeling; Molecular; Multi-Drug Resistance; Multiparity; Mutation; Neoplasm Metastasis; Normal Cell; Not Hispanic or Latino; Organoids; Outcome; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Pregnancy; Premalignant Cell; Primary Neoplasm; Public Health; Race; Reproductive History; Research; Resistance; Risk Factors; Scientist; Signal Transduction; Skin; Socioeconomic Status; Specimen; Stimulus; Stress; Stress Response Signaling; Stromal Neoplasm; Symptoms; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Treatment Efficacy; Tumor Stem Cells; Tumor-associated macrophages; United States; Variant; Woman; Work; Zoledronic Acid; aggressive breast cancer; aggressive therapy; biological adaptation to stress; cancer cell; cancer health disparity; cancer subtypes; cell immortalization; cohort; environmental agent; environmental change; epidemiology study; genetic signature; hazard; health disparity; high body mass index; in vivo Model; inflammatory breast cancer; intercellular communication; macrophage; malignant breast neoplasm; mammary; modifiable risk; molecular subtypes; monocyte; mouse model; neoplastic cell; novel; prevent; response; stem cells; stressor; targeted treatment; therapy outcome; trait; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumorigenic

Inflammatory breast cancer (IBC), the most lethal form of breast cancer, is a health disparity. IBC has a greater incidence and younger presentation in African Ancestry women (AA) compared with white women (W). IBC is also particularly aggressive in AA, who exhibit substantially shorter median survival compared to W, irrespective of molecular subtype. The underlying causes of this disparity in clinical outcome, much of which remains after controlling for medical coverage and treatment access, are poorly understood, severely limiting potential strategies to close this gap. Our proposed work addresses the critical, unanswered questions - What tumor biological mechanisms drive the more aggressive IBC biology in AA) and how can these mechanisms be modulated therapeutically? Our epidemiological studies identify that modifiable risk factors like reproductive factors (early age at first pregnancy, multiparity, and lack of breastfeeding) and high body mass index (BMI), are associated with poor therapeutic outcomes and survival among AA-IBC compared to W-IBC. These stressors have the potential to cause persistent inflammation in the mammary gland. A basic survival mechanism that is intrinsic in both normal and cancer cells is the ability to constantly respond and adapt to stress stimuli (like mutations, life-stressors, environmental changes, therapy) referred to as adaptive stress response (ASR). Linking these observations, is our identification of ASR gene sets in IBC cells exposed to stress stimuli that show race-specific differences in expression. These datasets lead to our overarching hypotheses that 1. a heightened adaptive stress response consisting of NFκB activation, suppression of programmed cell death, and pro-tumorigenic macrophages promotes outgrowth of invasive, metastatic and treatment resistant tumor cells in AA-IBC; 2. pharmacologic inhibition of the ASR pathway in conjunction with macrophage inhibition will suppress IBC growth and dissemination. To test this hypothesis, we propose Aims to (1) investigate whether AA- and W- derived normal breast epithelial cells and IBC cell lines promote monocyte differentiation using a panel of immortalized cell lines from core breast biopsies of AA and W healthy women and IBC cells in co-culture assays with monocytes and how ASR pro-survival markers correlate with stromal patterns of stem cells and macrophages in patient tissues by gene expression and immunohistochemistry analysis; (2) implant AA- and W- patient derived IBC cell lines with differential NFκB activity in a novel macrophage-induced “early lesion” murine model to spatially query tumor-stromal cell interactions and host macrophage infiltration during tumor initiation; (3) investigate the ability of clinically available agents, birinapant, a “cell death booster” and zoledronic acid, a macrophage depleting agent to inhibit growth of tumor organoids derived from AA-IBC drug resistant variants in the ‘early lesion’ murine model. Successful completion of this project will lead to new treatment options for IBC patients with a high unmet medical need. Importantly, new AA- and W- bio-specimens, PDX and derivative cell lines and IBC-specific models resulting from the proposed work will be available to the scientific community.

炎症性乳腺癌 (IBC) 是最致命的乳腺癌形式，是一种健康差异。中型散装容器 与白人女性相比，非洲裔女性 (AA) 的发病率更高且发病更年轻 （W）。 IBC 在 AA 中也特别具有攻击性，与 W 相比，AA 的中位生存期要短得多， 与分子亚型无关。造成临床结果差异的根本原因，其中大部分是 在控制了医疗覆盖和治疗可及性后，人们对这些问题的了解仍然很少，严重限制了 缩小这一差距的潜在策略。我们提出的工作解决了关键的、悬而未决的问题——什么 肿瘤生物学机制驱动 AA 中更具侵袭性的 IBC 生物学），这些机制如何 进行治疗调节？我们的流行病学研究发现，可改变的风险因素，如生殖 因素（首次怀孕年龄过早、多产和缺乏母乳喂养）和高体重指数（BMI）是 与 W-IBC 相比，AA-IBC 的治疗结果和生存率较差。这些压力源 有可能引起乳腺持续炎症。一个基本的生存机制是 正常细胞和癌细胞固有的能力是不断响应和适应压力刺激（如 突变、生活压力源、环境变化、治疗）称为适应性应激反应（ASR）。 将这些观察结果联系起来，我们对暴露于应激刺激的 IBC 细胞中的 ASR 基因组进行了鉴定，结果表明 种族特异性的表达差异。这些数据集得出我们的总体假设：1.a 增强的适应性应激反应，包括 NFκB 激活、程序性细胞死亡抑制和 促肿瘤巨噬细胞促进侵袭性、转移性和治疗耐药性肿瘤细胞的生长 AA-IBC； 2. ASR途径的药理学抑制与巨噬细胞抑制相结合将抑制 IBC 的增长和传播。为了检验这一假设，我们提出目标 (1) 研究 AA- 和 W- 衍生的正常乳腺上皮细胞和 IBC 细胞系使用一组促进单核细胞分化 来自 AA 和 W 健康女性核心乳房活检的永生化细胞系和共培养测定中的 IBC 细胞 与单核细胞的关系以及 ASR 促生存标记如何与干细胞和基质模式相关 通过基因表达和免疫组织化学分析患者组织中的巨噬细胞； (2) 种植体 AA- 和 W- 在新型巨噬细胞诱导的“早期病变”小鼠中，患者来源的 IBC 细胞系具有差异 NFκB 活性 在肿瘤发生过程中空间查询肿瘤-基质细胞相互作用和宿主巨噬细胞浸润的模型； (3) 研究临床可用药物 birinapant（一种“细胞死亡促进剂”）和唑来膦酸（一种 巨噬细胞耗竭剂可抑制源自 AA-IBC 耐药变体的肿瘤类器官的生长 “早期病变”小鼠模型。该项目的成功完成将为 IBC 带来新的治疗选择 医疗需求未得到满足的患者。重要的是，新的 AA- 和 W- 生物样本、PDX 和衍生细胞 拟议工作产生的线路和 IBC 特定模型将提供给科学界。