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: 9768359
• 负责人: Hector Luis Franco
• 金额: $ 25.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9768359
• 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; 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; Xenograft Model; Xenograft procedure; base; 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 therapeutics; overexpression; 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率的第二大原因，几乎75％ 诊断时表达雌激素受体-α（ER）。据估计，约有30-40％的ER+乳房 肿瘤通过从头开始或获得的抗性对马酮治疗具有抗性。最近的证据 表明炎症在促进发病机理和获得对同性子的耐药性方面起着关键作用 治疗，被认为是乳腺癌的危险因素。为此，我们和其他人发现了 通过 通过细胞因子诱导的ER的磷酸化和直接调节的ER和NFB之间的相互作用 ER先驱因子FOXA1。这很重要，因为大于80％的淋巴结转移和65- 在退休时，由ER+原发性肿瘤引起的远处转移中有70％保持ER表达。还， 炎症介质，例如细胞因子，例如肿瘤坏死因子α（TNF）或主转录 因子NFB及其上游调节剂IKK在乳腺肿瘤中高度存在，并且随肿瘤等级而增加。 我们将使用ER+乳腺癌患者衍生的Xenographictic（PDXS），而FACS分离（EPCAM+/CD49F）ER+ 从多个患者分离出的腔细胞，以了解炎症信号传导如何影响ER功能。我们的 假设是由NFB及其上游调节器IKK驱动的炎症信号传导导致ER改变 功能和靶基因表达，导致更具侵略性的肿瘤，并且对 内分泌疗法。首先，我们将定义原发性肿瘤的转录和表观遗传反应 雌激素和细胞因子的标本使用新的下一代测序诱导炎症信号传导 技术（例如gro-seq，atac-seq和chip-seq），我们将测试主要的人类肿瘤 标本，暴露于增加的增殖，侵袭，转移和对马内治疗的抵抗 暴露于雌激素和炎症细胞因子。我们还将测试IKK/NFB的新型抑制剂是否会营救 对肿瘤标本中赛马疗法的敏感性。对我们跨的数据的生物信息学分析 许多患者将允许我们识别潜在预后的生物标志物和/或基因特征 内分泌疗法和/或可能受益的患者的患者 NFB信号传导的抑制剂。下面列出的是我们3个特定目标的标题： 目标1：定义原代人中ER和NFB的转录变化和染色质结合曲线 响应E2和促炎细胞因子的组织。 AIM 2：确定基于炎症的乳腺肿瘤功能的生物学后果 目标3：定义原型特征，识别生物标志物并测量基于炎症的患病率 在患者样品中调节ER功能。