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