Project 2: Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer

项目2：基于炎症的乳腺癌激素治疗耐药机制

• 批准号: 10244930
• 负责人: Hector Luis Franco
• 金额: $ 27.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-05 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244930
• 关键词: ATAC-seq; Address; Affect; Aromatase Inhibitors; Binding; Binding Sites; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; Breast Cancer Patient; Breast Cancer Risk Factor; CCL2 gene; Cancer Etiology; Cell Culture Techniques; Cell Line; Cells; ChIP-seq; Chromatin; Clinical Data; Code; Data; Data Analyses; Data Set; Diagnosis; Disease; Distant Metastasis; Effectiveness; Endocrine; Enhancers; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Gene Expression; Genes; Genetic Transcription; Genome; Genomic approach; Genomics; Goals; Hormones; Human; Inflammation; Inflammation Mediators; Inflammatory; Link; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mediator of activation protein; Metastatic Neoplasm to Lymph Nodes; Modeling; Neoadjuvant Study; Neoplasm Metastasis; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Pharmacology; Phenotype; Phosphorylation; Play; Prevalence; Primary Neoplasm; Publishing; Relapse; Resistance; Role; Sampling; Series; Signal Transduction; Specimen; TACSTD1 gene; TNF gene; Tamoxifen; Technology; Testing; The Cancer Genome Atlas; Time; Untranslated RNA; Woman; base; biomarker signature; cytokine; genetic signature; genome-wide; genomic signature; global run on sequencing; hormone therapy; human tissue; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; migration; mortality; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; predict clinical outcome; prognostic; prognostic signature; response; transcription factor; tumor; tumor growth; tumorigenic

Project 2 Abstract Breast cancer is the second leading cause of cancer mortality in women and nearly 75% of breast tumors express estrogen receptor-α (ER) at the time of diagnosis. It is estimated that about 30-40% of ER+ breast tumors become resistant to hormone therapy, either through de novo or acquired resistance. Recent evidence suggests that inflammation plays a key role in promoting pathogenesis and acquired resistance to hormone therapies, and is considered a risk factor for breast cancer. To this end, we and others have uncovered an important mechanism linking inflammatory signaling to endocrine resistance in breast cancer through interactions between the ER and NFB, via cytokine-induced phosphorylation of ER and direct modulation of the ER pioneer factor FOXA1. This is important because greater than 80% of the lymph node metastases and 65– 70% of distant metastases arising from ER+ primary tumors retain ER expression at the time of relapse. Also, inflammatory mediators, such as cytokines like the tumor necrosis factor alpha (TNF) or the master transcription factor NFB and its upstream regulator IKK, are highly present in breast tumors and increase with tumor grade. We will use ER+ breast cancer patient-derived xenografts (PDXs), and FACS isolated (EpCAM+/CD49f) ER+ luminal cells isolated from multiple patients, to understand how inflammatory signaling affects ER function. Our hypothesis is that inflammatory signaling, driven by NFB and its upstream regulator IKK, leads to altered ER function and target gene expression resulting in more aggressive tumors and an increased resistance to endocrine therapy. First we will define the transcriptional and epigenetic response of the primary tumor specimens to estrogen and cytokine induced inflammatory signaling using novel next-generation sequencing technologies (such as GRO-seq, ATAC-seq and ChIP-seq) Then we will test if the primary human tumor specimens, exhibit increased proliferation, invasion, metastasis and resistance to hormone therapy when exposed to estrogen and inflammatory cytokines. We will also test if novel inhibitors of IKK/NFB will rescue sensitivity to hormone therapy in the tumor specimens. Bioinformatic analysis of the data we generate across many patients will allow us to identify biomarkers and/or gene signatures that are potentially prognostic of patients that have worse outcomes on endocrine therapies and/or predictive of patients who may benefit from inhibitors of NFB signaling. Listed below are the headings for our 3 specific aims: Aim 1:Define the transcriptional changes and chromatin binding profiles of ER and NFB in primary human tissues in response to E2 and proinflammatory cytokines. Aim 2:Determine the biological consequences of inflammation-based modulation of ER function in breast tumors Aim 3:Define prognostic signatures, identify biomarkers and measure prevalence of inflammation-based modulation of ER function across patient samples.

项目2 摘要 乳腺癌是女性癌症死亡的第二大原因，占乳腺肿瘤的近 75% 诊断时表达雌激素受体-α (ER)。据估计，大约 30-40% ER+ 乳房 肿瘤对激素治疗产生耐药性，无论是通过新生耐药还是获得性耐药。最近的证据 表明炎症在促进发病机制和获得性激素抵抗方面发挥着关键作用 疗法，并被认为是乳腺癌的危险因素。为此，我们和其他人发现了一个 将炎症信号传导与乳腺癌内分泌抵抗联系起来的重要机制 ER 和 NFκB 之间的相互作用，通过细胞因子诱导的 ER 磷酸化和直接调节 ER先锋因子FOXA1。这很重要，因为超过 80% 的淋巴结转移和 65- 70% 由 ER+ 原发肿瘤引起的远处转移在复发时保留 ER 表达。还， 炎症介质，例如肿瘤坏死因子 α (TNF) 等细胞因子或主转录因子 因子 NFB 及其上游调节因子 IKK 在乳腺肿瘤中高度存在，并随着肿瘤分级而增加。 我们将使用 ER+ 乳腺癌患者来源的异种移植物 (PDX) 和 FACS 分离的 (EpCAM+/CD49f) ER+ 从多名患者身上分离出管腔细胞，以了解炎症信号如何影响内质网功能。我们的 假设是由 NFκB 及其上游调节因子 IKK 驱动的炎症信号传导导致 ER 改变 功能和靶基因表达导致更具侵袭性的肿瘤和增强的耐药性 内分泌治疗。首先我们将定义原发肿瘤的转录和表观遗传反应 使用新型下一代测序技术对样本进行雌激素和细胞因子诱导的炎症信号传导 技术（例如GRO-seq、ATAC-seq和ChIP-seq）然后我们将测试原发性人类肿瘤是否 标本表现出增加的增殖、侵袭、转移和对激素治疗的抵抗力 暴露于雌激素和炎症细胞因子。我们还将测试 IKK/NFB 的新型抑制剂是否能够拯救 肿瘤标本中对激素治疗的敏感性。对我们生成的数据进行生物信息分析 许多患者将允许我们识别可能预测预后的生物标志物和/或基因特征 内分泌治疗结果较差的患者和/或预测可能受益的患者 NF+B 信号传导抑制剂。下面列出了我们 3 个具体目标的标题： 目标 1：定义原代人类中 ER 和 NF+B 的转录变化和染色质结合谱 组织对 E2 和促炎细胞因子的反应。 目标 2：确定乳腺肿瘤中基于炎症的 ER 功能调节的生物学后果 目标 3：定义预后特征、识别生物标志物并测量基于炎症的患病率 跨患者样本的 ER 功能调节。