Molecular Determinants of Health Disparities in Inflammatory Breast Cancer

炎症性乳腺癌（IBC）是乳腺癌中最致命的形式，是一种健康差异。IBC 与白色女性相比，非洲裔女性（AA）的发病率更高，表现更年轻 （W）. IBC在AA中也特别具有侵袭性，与W相比，AA表现出明显更短的中位生存期， 而与分子亚型无关。这种临床结果差异的根本原因，其中大部分是 在控制了医疗保险和治疗机会之后，仍然缺乏了解，严重限制了 缩小这一差距的潜在战略。我们提出的工作解决了关键的，未回答的问题-什么 肿瘤生物学机制驱动AA中更具侵袭性的IBC生物学），以及这些机制如何 调节治疗？我们的流行病学研究表明，可改变的风险因素，如生殖 因素（首次怀孕年龄小、多胎、缺乏母乳喂养）和高体重指数（BMI）， 与W-IBC相比，AA-IBC的治疗结局和生存率较差。这些压力源 有可能导致乳腺持续炎症。一种基本的生存机制， 正常细胞和癌细胞的内在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，是我们在暴露于应激刺激的IBC细胞中鉴定出的ASR基因组， 种族特异性表达差异。这些数据集导致我们的总体假设，1。一 增强的适应性应激反应，包括NFκB活化、抑制程序性细胞死亡，以及 促肿瘤发生巨噬细胞促进侵袭性、转移性和治疗抗性肿瘤细胞的生长， AA-IBC; ASR途径的药理学抑制与巨噬细胞抑制一起将抑制 IBC的增长和传播。为了验证这一假设，我们提出的目的是（1）调查是否AA-和W- 衍生的正常乳腺上皮细胞和IBC细胞系促进单核细胞分化， 来自AA和W健康女性的核心乳腺活检组织的永生化细胞系和共培养测定中的IBC细胞 以及ASR促生存标记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在患者组织中的巨噬细胞;（2）植入AA-和W- 在一种新的巨噬细胞诱导的“早期病变”小鼠中具有不同NFκB活性的患者来源的IBC细胞系 在肿瘤起始期间空间查询肿瘤-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“细胞死亡助推剂”）和唑来膦酸（一种 巨噬细胞消耗剂以抑制源自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 有高度未满足医疗需求的患者。重要的是，新的AA-和W-生物标本、PDX和衍生细胞 将向科学界提供拟议工作产生的路线和国际生物多样性公约专用模型。

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.