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: 10306034
• 负责人: Gayathri Devi
• 金额: $ 51.83万
• 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/10306034
• 关键词: Address; Affect; African; African American; 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）是乳腺癌最致命的形式，是健康差异。 IBC 与白人妇女相比 （W）。 IBC在AA中也特别具有侵略性，与W相比，他的中位生存率大大较短。 无论分子亚型如何。这种临床结果差异的根本原因，其中很多 控制医疗覆盖范围和治疗访问后，仍然存在不理解，严重限制 缩小这一差距的潜在策略。我们提出的工作解决了关键，未解决的问题 - 什么 肿瘤生物学机制驱动AA中的IBC生物学越积极，这些机制如何 理论上调制？我们的流行病学研究确定了可修改的危险因素，例如生殖 因素（初次怀孕，多重性和缺乏母乳喂养的年龄）和高体重指数（BMI）是 与W-IBC相比，与AA-IBC的治疗结果和生存率差有关。这些压力源 有可能引起乳腺持续性炎症。一种基本的生存机制 正常和癌细胞的固有性是不断反应和适应应力刺激的能力（例如 突变，生命应力，环境变化，治疗）称为适应性应激反应（ASR）。 链接这些观察结果是我们对暴露于应力刺激的IBC细胞中ASR基因集的识别 表达中的种族特异性差异。这些数据集导致我们的总体假设1。 由NFκB激活，抑制程序性细胞死亡和 促肿瘤巨噬细胞促进侵入性，转移和治疗性肿瘤细胞的生长 AA-IBC; 2。与巨噬细胞抑制对ASR途径的药理抑制作用将抑制 IBC的增长和传播。为了检验这一假设，我们提出旨在（1）研究AA和W-是否是否 衍生的正常乳房上皮细胞和IBC细胞系使用一组面板促进单核细胞分化 在共培养分析中，来自AA和W健康女性和IBC细胞的核心乳房活检的永生细胞系 与单核细胞以及ASR促生存标志物如何与干细胞的基质模式相关 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）植入AA和W- 患者在新型巨噬细胞引起的“早期病变”鼠中衍生具有差异NFκB活性的IBC细胞系 在肿瘤开始期间，在空间查询肿瘤 - 核细胞相互作用和宿主巨噬细胞浸润的模型； （3）研究临床上可用的药物，Birinapant，“细胞死亡助推器”和唑来膦酸的能力，A 巨噬细胞耗尽剂抑制源自AA-IBC药物抗性变异体的肿瘤器官的生长 “早期病变”鼠模型。成功完成该项目将为IBC提供新的治疗选择 高未满足医疗需求的患者。重要的是，新的AA和W-BIO规范，PDX和衍生细胞 拟议工作产生的线条和IBC特定模型将提供给科学界。