Erythropoietin receptors in breast cancer

乳腺癌中的促红细胞生成素受体

• 批准号: 6854582
• 负责人: MURAT O ARCASOY
• 金额: $ 28.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854582
• 关键词: MCF7 cell; angiogenesis; athymic mouse; biological signal transduction; breast neoplasms; cell proliferation; clinical research; erythropoietin; growth factor receptors; human tissue; hypoxia; immunocytochemistry; laboratory rat; molecular oncology; monoclonal antibody; neoplastic growth; neutralizing antibody; protein structure function; receptor expression; xenotransplantation

DESCRIPTION (provided by applicant): The objective of this proposal is to investigate erythropoietin (EPO) and erythropoietin receptor (EpoR) expression and function in the pathobiology breast cancer. EPO is a hypoxia-inducible glycoprotein hormone that is the principal hematopoietic cytokine regulating the production of red blood cells by binding to its specific cell surface receptor EpoR, a member of the Type I cytokine receptor family. Recombinant human EPO is widely used in patients with cancer for treatment or prevention of anemia associated with chemotherapy and radiation therapy. Recent studies in our laboratory revealed high levels of functional EpoR expression in breast cancer cells. Induction of EpoR expression was observed in human mammary epithelial cells and characterization of the structure of EpoRs revealed the expression of novel EpoR mRNA isoforms in breast cancer. The co-expression of EpoR and its ligand EPO in tumor cells suggested the potential for generation of an autocrine or paracrine growth stimulatory loop. Inhibition of EpoR signaling in vitro or in vivo resulted in decreased proliferation of breast cancer cells suggesting the presence of a previously unknown, functional role for EpoR signaling in the pathobiology of breast cancer. The studies in this proposal will aim to (1) Characterize the role of EPO-EpoR expression and signaling in the proliferation of breast cancer cells and induction of tumor angiogenesis in vivo (2) Investigate the ability of EpoR-mediated signaling to stimulate the proliferation of primary human mammary epithelial cells and (3) Determine whether EPO-EpoR over-expression is coupled to tumor hypoxia and serves as an adverse prognostic factor in patients with breast cancer. We propose to study mechanisms of EPO-EpoR expression and activation in breast cancer cells and investigate the role of EPO-EpoR in tumor growth and angiogenesis using well-established human breast cancer xenografis and rodent mammary windows for orthotopic breast cancer. We will over-express EpoR in primary human mammary epithelial cells (HMECs) to investigate the activation of EpoR signaling pathways in HMECs and the effects on cellular proliferation in an experimental model of early mammary carcinogenesis. We will characterize the role of tumor hypoxia in EPO-EpoR over-expression in primary breast tumors pre-labeled with a cellular hypoxia marker. We shall determine the utility of high levels of EPO-EpoR co-expression in primary tumors as a prognostic factor that may be linked to an unfavorable disease-free and overall survival in patients with breast cancer. It is anticipated that the findings of these studies will contribute to our understanding of the role of EPO and EpoR in the pathobiology of breast cancer and may lead to the formulation of new therapeutic strategies targeted against EpoR function in the future.

描述（由申请人提供）：该提案的目的是研究促性促红细胞生成素（EPO）和促红细胞生成素受体（EPOR）的表达和功能。 EPO是一种低氧诱导的糖蛋白激素，是主要造血细胞因子，通过与I型细胞因子受体家族的成员结合，可通过与其特异性细胞表面受体EPOR结合来调节红细胞的产生。重组人EPO被广泛用于癌症患者，以治疗或预防与化学疗法和放射治疗相关的贫血。我们实验室的最新研究表明，乳腺癌细胞中高水平的功能EPOR表达。在人类乳腺上皮细胞中观察到Epor表达的诱导，并且表征Epors的结构揭示了乳腺癌中新型Epor mRNA同工型的表达。肿瘤细胞中EPOR及其配体EPO的共表达表明，产生自分泌或旁分泌生长刺激环的潜力。在体外或体内抑制EPOR信号传导导致乳腺癌细胞的增殖降低，这表明存在Epor信号在乳腺癌病理生物学中的先前未知的功能作用。 The studies in this proposal will aim to (1) Characterize the role of EPO-EpoR expression and signaling in the proliferation of breast cancer cells and induction of tumor angiogenesis in vivo (2) Investigate the ability of EpoR-mediated signaling to stimulate the proliferation of primary human mammary epithelial cells and (3) Determine whether EPO-EpoR over-expression is coupled to tumor hypoxia and serves as an adverse prognostic乳腺癌患者的因素。我们建议研究乳腺癌细胞中的epo- ep-表达和激活的机制，并使用良好成熟的人类乳腺癌Xenografis和啮齿动物乳腺窗口对正直乳腺癌研究Epo-Epor在肿瘤生长和血管生成中的作用。我们将在原代人乳腺上皮细胞（HMEC）中过表达EPOR，以研究HMEC中EPOR信号通路的激活以及对早期乳腺癌作用的实验模型中对细胞增殖的影响。我们将表征肿瘤缺氧在用细胞缺氧标记预先标记的原发性乳腺肿瘤中的肿瘤缺氧中的作用。我们将确定原发性肿瘤中高水平的EPO-EPOR共表达的效用，这可能与乳腺癌患者的不利疾病和整体生存有关的预后因素。预计这些研究的结果将有助于我们理解EPO和EPOR在乳腺癌病理生物学中的作用，并可能导致未来针对EPOR功能的新治疗策略的制定。