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

探索雌激素受体β在炎症性乳腺癌进展和转移中的作用

• 批准号: 9885851
• 负责人: Christoforos Thomas
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9885851
• 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; Epithelium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen receptor positive; 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; 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; 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; outcome forecast; overexpression; preclinical study; prevent; receptor; receptor expression; rho GTP-Binding Proteins; targeted treatment; therapeutic target; tumor

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，中位生存率约为4年 与其他形式的乳腺癌相比超过10年。预后不良与高有关 这些肿瘤的倾向是发展遥远的转移酶。尽管某些分子发生了较高的事件 IBC的改变，基因分析研究未能识别特定的治疗靶标，并且有 目前尚无对该疾病独特的FDA批准的靶向疗法。大多数IBC肿瘤缺乏 雌激素受体α（ERα）表明ERβ的潜力介导这些肿瘤中雌激素的作用。 与致癌ERα不同，ERβ与上皮分化和非IBC的侵袭有关。 为了研究ERβ在IBC中是否具有相似的作用，我们分析了人类肿瘤组织和数据集。我们的 发现是第一个指示在超过50％的IBC和接收方相关性中表达ER的表达 拥有更好的生存。为了研究这种关联是否反映了ERβ抑制转移的能力，我们 IBC的临床前模型。 IBC细胞中ER的敲除通过细胞骨架重塑促进 迁移并激活与IBC中细胞运动和转移相关的RHOC等分子。 相反，激活ER潜在其抗迁移活性的配体。与体外抗 - 一致 迁移活性，ERβ熟练的细胞在初步分析期间的转移性比ERβ基因敲除细胞少。 IBC的原位和肺定植模型。因此，我们假设ERβ及其激动剂 IBC肿瘤的预防进展和转移。我们提出的研究将：1）确定ERβ的作用 及其在IBC的进展和转移方面的激动剂，2）阐明了抗变形的机制 ERβ的活性和3）检查ERβ是否与IBC中的转移相关。调查 ERβ在IBC转移中的作用，我们将研究受体如何改变IBC细胞的转移电位 体外和体内肿瘤。我们还将评估目前处于临床的ERβ配体的效率 试验，以抑制IBC Xenographtics的转移，以确保我们的研究会影响IBC的临床治疗 （目标1）。此外，我们将通过分析特定途径来描述ERβ作用的分子机制 在疾病进展和转移中暗示的（AIM 2）。最后，我们将分析临床样本 验证ERβ在肿瘤中的表达，并验证其与转移的逆相关性（AIM 3）。通过定义 ERβ及其相关途径在IBC的进展和转移中的作用我们的研究将提供 对IBC生物学的见解，并有助于更好地理解为什么这些肿瘤会变成转移性。我们的 研究还将通过将ERβ建立为一种新颖的特定疗法，从而具有重要的临床意义。 目标是使IBC患者受益。我们的发现可以直接转化为临床环境中的进步 因为它们将验证一种新的治疗化合物，即单独或组合的ERβ配体 使用其他药物可以第二次抑制IBC转移并消除其相关的死亡率。