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

基本信息

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
项目类别：
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

项目摘要

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。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，无论分子亚型如何，造成临床结果差异的根本原因都是如此。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，严重限制了我们提出的工作解决了关键的、尚未解答的问题——什么是缩小这一差距的潜在策略。肿瘤生物学机制驱动 AA 中更具侵袭性的 IBC 生物学），这些机制如何我们的流行病学研究确定了可改变的危险因素，例如生殖因素（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，这些压力因素与 AA-IBC 的不良治疗结果和生存率相关。有可能引起乳腺持续炎症，这是一种基本的生存机制。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，结果表明这些数据集得出了我们的总体假设：1.a 血腥的适应性应激反应，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途径的药理抑制与巨噬细胞抑制相结合将抑制为了检验这一假设，我们提出的目标是 (1) 研究 AA- 和 W- 是否存在。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 健康女性核心乳腺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）植入物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”小鼠模型的成功完成将为 IBC 带来新的治疗选择。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。