Exploring the role of estrogen receptor beta in progression and metastasis ofInflammatory breast cancer

探讨雌激素受体β在炎症性乳腺癌进展和转移中的作用

基本信息

批准号：
10615449
负责人：
Christoforos Thomas
金额：
$ 24.09万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615449
关键词：
AKT1 gene Actins Affect Age Agonist Architecture Biology Breast Cancer Cell Breast Cancer Genetics Breast Cancer Patient Breast cancer metastasis Cell Adhesion Cell Culture System Cell physiology Cells Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Cytoskeleton Data Set Disease Disease Progression Distant Metastasis Ensure Epithelial Estrogen Receptor alpha Estrogen Receptor beta Estrogens FDA approved Foundations G-Protein-Coupled Receptors Genes Grant Guanine Nucleotide Exchange Factors Human In Vitro Incidence Knock-out Ligands Malignant Neoplasms Mediating Modeling Molecular Molecular Profiling Neoplasm Metastasis Newly Diagnosed Nonmetastatic Oncogenic Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Pre-Clinical Model Preventive treatment Prognosis Reagent Receptor Activation Reporting Research Role Sampling Signal Pathway Signal Transduction Specimen Translating Tumor Cell Line Tumor Tissue Xenograft Model Xenograft procedure base cell motility differential expression efficacy evaluation genetic profiling improved in vivo inflammatory breast cancer innovation insight lung colonization malignant breast neoplasm metastatic process migration mortality new therapeutic target novel novel therapeutics overexpression preclinical study prevent receptor receptor expression rho GTP-Binding Proteins targeted treatment therapeutic target tumor

项目摘要

Abstract Inflammatory breast cancer (IBC) is the most lethal form of breast cancer with median survival of about 4 years compared with more than 10 years for other forms of breast cancer. Poor prognosis is associated with the high propensity of these tumors to develop distant metastases. Despite a higher incidence of certain molecular alterations in IBC, genetic profiling studies have failed to identify a specific therapeutic target and there are currently no FDA-approved targeted therapies that are unique for the disease. The majority of IBC tumors lack estrogen receptor α (ERα) suggesting the potential of ERβ to mediate effects of estrogen in these tumors. Unlike the oncogenic ERα, ERβ is associated with epithelial differentiation and decreased invasion in non-IBC. To investigate whether ERβ has a similar role in IBC, we analyzed human tumor tissues and datasets. Our findings are the first to indicate expression of ER in more than 50% of IBCs and correlation of the receptor with better survival. To investigate whether this association reflects the ability of ERβ to inhibit metastasis, we studied preclinical models of IBC. Knockout of ER in IBC cells promotes through cytoskeleton remodeling migration and activates molecules such as RhoC that are associated with cell motility and metastasis in IBC. Conversely, ligands that activate ER potentiate its anti-migratory activity. Consistent with the in vitro anti- migratory activity, ERβ proficient cells are less metastatic than ERβ knockout cells during preliminary analysis of orthotopic and lung colonization models of IBC. We, therefore, hypothesize that ERβ and its agonists prevent progression and metastasis of IBC tumors. Our proposed research will: 1) determine the role of ERβ and its agonists in progression and metastasis of IBC, 2) elucidate the mechanism of the anti-metastatic activity of ERβ and 3) examine whether ERβ is inversely associated with metastasis in IBC. To investigate the role of ERβ in metastasis of IBC, we will examine how the receptor alters the metastatic potential of IBC cells and tumors in vitro and in vivo. We will also evaluate the efficacy of ERβ ligands, that are currently in clinical trials, to inhibit metastasis of IBC xenografts ensuring that our studies will impact the clinical treatment of IBC (Aim 1). Further, we will delineate the molecular mechanisms of ERβ action by analyzing specific pathways that are implicated in disease progression and metastasis (Aim 2). Finally, we will analyze clinical samples to validate the expression of ERβ in tumors and verify its inverse association with metastasis (Aim 3). By defining the role of ERβ and its associated pathways in progression and metastasis of IBC our research will provide insights into the biology of IBC and assist to better understand why these tumors become metastatic. Our study will also have important clinical implications by establishing ERβ as a novel and specific therapeutic target that benefits patients with IBC. Our findings can directly be translated into advances in clinical setting because they will validate a new therapeutic compound, the ERβ ligands, that either alone or in combination with other drugs can substantially repress IBC metastasis and eliminate its associated mortality.

抽象的炎性乳腺癌 (IBC) 是最致命的乳腺癌形式，中位生存期约为 4 年与其他形式的乳腺癌相比，10年以上的预后较差。尽管某些分子的发生率较高，但这些肿瘤有发生远处转移的倾向。 IBC 的改变，基因谱研究未能确定特定的治疗靶点，并且有目前尚无 FDA 批准的针对该疾病的独特靶向疗法。大多数 IBC 肿瘤缺乏。雌激素受体 α (ERα) 表明 ERβ 在这些肿瘤中介导雌激素作用的潜力。与致癌 ERα 不同，ERβ 与非 IBC 中的上皮分化和侵袭减少相关。为了研究 ERβ 在 IBC 中是否具有类似的作用，我们分析了人类肿瘤组织和数据集。研究结果首次表明 ER 在超过 50% 的 IBC 中表达以及受体的相关性为了研究这种关联是否反映了 ERβ 抑制转移的能力。研究了 IBC 的临床前模型。IBC 细胞中 ER 的敲除通过细胞骨架重塑来促进。迁移并激活与 IBC 中细胞运动和转移相关的分子，例如 RhoC。离线时，激活 ER 的配体增强其抗迁移活性，与体外抗迁移活性一致。迁移活性，初步分析期间 ERβ 熟练细胞的转移性低于 ERβ 敲除细胞因此，我们捕获了 ERβ 及其激动剂。预防 IBC 肿瘤的进展和转移我们提出的研究将： 1) 确定 ERβ 的作用。及其激动剂在 IBC 进展和转移中的作用，2）阐明抗转移机制 ERβ 的活性，3) 检查 ERβ 是否与 IBC 的转移呈负相关。 ERβ在IBC转移中的作用，我们将研究受体如何改变IBC细胞的转移潜力我们还将评估目前处于临床阶段的 ERβ 配体的功效。抑制 IBC 异种移植物转移的试验，确保我们的研究将影响 IBC 的临床治疗（目标 1）进一步，我们将通过分析特定途径来描述 ERβ 作用的分子机制。最后，我们将分析临床样本以了解与疾病进展和转移有关的因素。验证肿瘤中 ERβ 的表达并验证其与转移的负相关性（目标 3）。我们的研究将提供 ERβ 及其相关途径在 IBC 进展和转移中的作用深入了解 IBC 的生物学特性，有助于更好地理解这些肿瘤为何会发生转移。通过将 ERβ 确立为一种新型且特异性的治疗方法，该研究还将具有重要的临床意义。我们的研究结果可以直接转化为临床环境的进步。因为他们将验证一种新的治疗化合物，即 ERβ 配体，无论是单独使用还是组合使用与其他药物联合使用可以显着抑制 IBC 转移并消除其相关的死亡率。