Roles of RORalpha in breast cancer development and progression

RORalpha 在乳腺癌发生和进展中的作用

• 批准号: 10440464
• 负责人: Ren Xu
• 金额: $ 22.68万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440464
• 关键词: 3-Dimensional; Agonist; Biological Assay; Biology; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Epithelial Cells; Cell Polarity; Cellular Metabolic Process; Chronic; Coculture Techniques; Complex; Development; Down-Regulation; Epithelial Cells; Gene Expression; Gene Expression Profiling; Generations; Glutathione Disulfide; Goals; Human; Hydrogen Peroxide; Immunocompetent; Infiltration; Inflammation; Knockout Mice; Knowledge; Lead; Link; Malignant Neoplasms; Measurement; Mediating; Metabolic; Metformin; Mitochondria; Modeling; Molecular; Mus; NADP; Nature; Neoplasm Metastasis; Nuclear Orphan Receptor; Oxidation-Reduction; Pathway interactions; Positioning Attribute; Production; Reactive Oxygen Species; Research; Role; Scheme; Source; Structure; Superoxides; System; TP53 gene; Testing; Tissue Microarray; Tissues; Tumor Suppressor Proteins; base; breast cancer progression; cancer cell; cancer prevention; cancer therapy; cytokine; druggable target; healing; improved; inhibitor; insight; knock-down; loss of function; macrophage; malignant breast neoplasm; mammary; metabolomics; monocyte; multidisciplinary; novel; novel strategies; stable isotope; transcriptome; translational potential; tumor; tumor microenvironment; tumor progression; wound

ABSTRACT Tumor has been described as the wounds that do not heal. The two share some common features, such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarity induced macrophage infiltration. However, little is known of how disruption of epithelial cell polarity at early stage of breast cancer development induces macrophage infiltration. We have identified the RAR-related orphan nuclear receptor α (RORα) as a potent tumor suppressor by analyzing global gene expression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show that RORα inhibits ROS generation and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggest that RORα is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found that knockdown of RORα significantly induced ROS production in mammary epithelial cells. Reactive oxygen species (ROS) are the driver of cancer progression and critical regulator of the NF-κB pathway. Based on these novel findings, the central hypothesis of our proposal is that downregulation of RORα in non-polarized breast cancer cells increased ROS generation in mitochondria, thereby inducing NF-κB and macrophage infiltration. We integrate high-throughput metabolic analysis, a novel 3D co-culture system, and global gene expression profiling to delineate mechanisms by which RORα inhibits ROS production and macrophage infiltration. The long-term goal of this proposal is to define the impact of the RORα/ROS axis in mediating mammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposed following specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORα reduces ROS levels and NF-κB activity in polarized mammary epithelial cells; Aim 2. To determine how reduced RORα expression in non-polarized breast cancer cells induces macrophage infiltration and M2 polarization; Aim 3. Define the impact of RORα in suppressing breast cancer formation and metastasis. The proposed study is high impact for its inherent scientific importance and its translational potential. This study will elucidate the molecular mechanism by which disruption of tissue polarity induces macrophage infiltration/differentiation. Determining roles of RORα in reducing ROS generation and inhibiting NF-κB activation may identify a novel strategy to inhibit breast cancer development and progression.

抽象的 肿瘤被描述为无法愈合的伤口。这两个共享一些共同的功能，例如 极化组织结构和慢性感染的丧失。我们表明组织极性的破坏 诱导的巨噬细胞浸润。但是，几乎不知道早期上皮细胞极性如何破坏 乳腺癌发育的阶段诱导巨噬细胞浸润。我们已经确定了与RAR相关的 孤儿核接收器α（RORα）通过分析的全球基因表达谱作为有效的肿瘤抑制器 在极化和非极化乳腺上皮细胞中。我们最近的发现表明RORα抑制ROS 合成小鼠乳腺肿瘤模型中的产生和巨噬细胞浸润。这些结果表明 该RORα是乳腺上皮细胞中巨噬细胞浸润的有效抑制剂。我们发现 RORα的敲低可显着诱导乳腺上皮细胞的ROS产生。活性氧 物种（ROS）是癌症进展的驱动力和NF-κB途径的关键调节剂。基于 这些新的发现，我们提议的中心假设是，非偏振的RORα下调 乳腺癌细胞增加了线粒体中ROS的产生，从而诱导NF-κB和巨噬细胞 浸润。我们整合了高通量代谢分析，一种新型的3D共培养系统和全球基因 表达分析到描述RORα抑制ROS产生和巨噬细胞的机制 浸润。该提案的长期目标是定义RORα/ROS轴的影响 乳腺上皮细胞巨噬细胞串扰和控制乳腺癌的进展。我们提出了 以下特定旨在检验假设的特定目的：目的1。阐明RORα的分子机制 降低了极化乳腺上皮细胞中的ROS水平和NF-κB活性；目标2。确定如何 降低了非极化乳腺癌细胞中的RORα表达可诱导巨噬细胞浸润和M2 极化;目标3。定义RORα对抑制乳腺癌形成和转移的影响。这 拟议的研究对其继承的科学重要性及其翻译潜力具有很高的影响。这项研究会 阐明组织极性破坏引起巨噬细胞的分子机制 浸润/分化。确定RORα在减少ROS产生和抑制NF-κB中的作用 激活可能会确定一种抑制乳腺癌发展和进展的新型策略。