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: 10062495
• 负责人: Christoforos Thomas
• 金额: $ 37.04万
• 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/10062495
• 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.

摘要 炎症性乳腺癌(IBC)是最致命的乳腺癌，中位生存期约4年。 相比之下，其他形式的乳腺癌患者的患病时间超过10年。预后不良与高血压症有关 这些肿瘤发生远处转移的倾向。尽管某些分子的发病率较高 IBC的改变，基因图谱研究未能确定特定的治疗靶点，而且有 目前还没有FDA批准的针对这种疾病的独特靶向疗法。大多数IBC肿瘤缺乏 雌激素受体α(ERα)提示ERβ在这些肿瘤中可能介导雌激素的作用。 与致癌的ERα不同，ERβ与非IBC的上皮分化和侵袭性降低有关。 为了研究ERβ是否在结肠腺癌中具有类似的作用，我们分析了人类肿瘤组织和数据集。我们的 首次发现ER在超过50%的IBCs中的表达及其与受体的相关性 有了更好的生存。为了研究这种关联是否反映了ERβ抑制转移的能力，我们 研究了IBC的临床前模型。外周血细胞ER基因敲除通过细胞骨架重塑促进 迁移并激活与IBC中的细胞运动和转移相关的分子，如RhoC。 相反，激活ER的配体可以增强其抗迁移活性。与体外抗-DNA抗体一致 迁移活性，在初步分析中，ERβ熟练细胞比ERβ基因敲除细胞转移更少 IBC原位和肺定植模型的研究。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 2)阐明其抗肿瘤转移的作用机制 ERβ的活性；3)检测ERβ是否与IBC的转移呈负相关。为了调查 ERβ在外周血细胞转移中的作用，我们将研究受体如何改变外周血细胞的转移潜能 以及体内和体外的肿瘤。我们还将评估目前正在临床使用的ERβ配体的疗效 抑制IBC异种移植转移的试验，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的途径来描述ERβ作用的分子机制 与疾病进展和转移有牵连(目标2)。最后，我们将分析临床样本以 验证ERβ在肿瘤中的表达，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ER-β及其相关通路在IBC进展和转移中的作用 对IBC生物学的洞察，并有助于更好地了解这些肿瘤转移的原因。我们的 这项研究也将具有重要的临床意义，将ERβ建立为一种新的和特异的治疗方法 使IBC患者受益的目标。我们的发现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，ERβ配体，无论是单独还是组合 与其他药物联用可显著抑制IBC转移并消除其相关死亡率。