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: 10304897
• 负责人: Christoforos Thomas
• 金额: $ 13.64万
• 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 2022-02-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304897
• 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

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 相比之下，其他形式的乳腺癌则需要 10 多年的时间。预后不良与高 这些肿瘤发生远处转移的倾向。尽管某些分子的发生率较高 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。我们的 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 具有更好的生存能力。为了研究这种关联是否反映了 ERβ 抑制转移的能力，我们 研究了 IBC 的临床前模型。 IBC 细胞中 ER 的敲除可促进细胞骨架重塑 迁移并激活与 IBC 中细胞运动和转移相关的分​​子，例如 RhoC。 相反，激活 ER 的配体会增强其抗迁移活性。与体外抗病毒一致 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 IBC 的原位和肺定植模型。因此，我们假设 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 转移呈负相关。为了调查 ERβ在IBC转移中的作用，我们将研究受体如何改变IBC细胞的转移潜力 以及体外和体内的肿瘤。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）。此外，我们将通过分析特定途径来描述 ERβ 作用的分子机制 与疾病进展和转移有关（目标 2）。最后，我们将分析临床样本 验证肿瘤中 ERβ 的表达并验证其与转移的负相关性（目标 3）。通过定义 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。我们的 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。 使 IBC 患者受益的目标。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。