Molecular Determinants of Health Disparities in Inflammatory Breast Cancer

炎症性乳腺癌(IBC)是最致命的乳腺癌形式，是一种健康差异。IBC 与白人妇女相比，非洲血统妇女(AA)的发病率更高，表现更年轻 (W)。IBC在AA中也特别积极，与W相比，AA的中位生存期要短得多， 与分子亚型无关。临床结果差异的根本原因，其中很大一部分 在控制医疗覆盖范围和治疗途径后的遗体，人们了解很少，严重限制了 缩小这一差距的潜在战略。我们提议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)，这些机制如何 治疗上的调节？我们的流行病学研究发现，生殖等可改变的危险因素 因素(第一次怀孕的早期年龄、多胎和没有母乳喂养)和高体重指数(BMI)是 与W-IBC相比，AA-IBC的治疗结果和存活率较差。这些压力源 有可能导致乳腺持续发炎。一个基本的生存机制是 无论是正常细胞还是癌细胞，都具有不断响应和适应压力刺激的能力(如 突变、生活应激源、环境变化、治疗)称为适应性应激反应(ASR)。 与这些观察相联系的是，我们对暴露于应激刺激的IBC细胞中的ASR基因集进行了鉴定，表明 表达因种族而异的差异。这些数据集导致了我们的总体假设：1.a 增强的适应性应激反应，包括核因子κB的激活，抑制程序性细胞死亡，以及 促肿瘤巨噬细胞促进侵袭性、转移性和耐药肿瘤细胞的生长 Aa-ibc；2.对asr途径的药物抑制与巨噬细胞抑制相结合将抑制 IBC的增长和传播。为了验证这一假设，我们提出的目标是(1)调查AA-和W- 来源的正常乳腺上皮细胞和IBC细胞系通过一组 AA和W健康女性乳腺核心活检永生化细胞系与IBC细胞共培养实验 以及ASR促生存标志物如何与干细胞的基质模式和 患者组织中巨噬细胞的基因表达和免疫组化分析；(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，患者来源的具有不同核因子κB活性的IBC细胞系 肿瘤起始期间肿瘤-间质细胞相互作用和宿主巨噬细胞侵袭的空间查询模型 (3)研究临床上可用的药物，比利奈帕特，“细胞死亡促进剂”和唑来膦酸， 巨噬细胞清除剂抑制AA-IBC耐药变异体肿瘤细胞生长的实验研究 “早期损伤”小鼠模型。该项目的成功完成将为IBC带来新的治疗选择 有高度未得到满足的医疗需求的患者。重要的是，新的AA和W生物样本，PDX和衍生细胞 将向科学界提供拟议工作产生的LINES和IBC特定模型。

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.