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.

摘要 肿瘤被描述为无法愈合的伤口。两者有一些共同的特点，如 极化组织结构的丧失和慢性炎症。我们发现组织极性的破坏 诱导巨噬细胞浸润。然而，很少有人知道如何破坏上皮细胞极性在早期， 乳腺癌发展阶段诱导巨噬细胞浸润。我们已经确定了与RAR相关的 孤儿核受体α（RORα）作为一种有效的肿瘤抑制因子，通过分析全局基因表达谱 在极化和非极化的乳腺上皮细胞中。我们最近的研究结果表明，RORα抑制ROS 在同基因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 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的敲低显著诱导乳腺上皮细胞中ROS的产生。活性氧 活性氧（ROS）是癌症进展的驱动因素和NF-κB途径的关键调节因子。基于 这些新的发现，我们的建议的中心假设是，在非极化的RORα下调， 乳腺癌细胞增加线粒体中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共培养系统和全局基因 表达谱描绘RORα抑制ROS产生和巨噬细胞 浸润该提案的长期目标是确定RORα/ROS轴在介导 乳腺上皮细胞-巨噬细胞串扰和调节乳腺癌进展。我们提出 以下具体目标来测试假设：目标1。为了阐明RORα 降低极化乳腺上皮细胞中的ROS水平和NF-κB活性;目的2.以确定如何 非极化乳腺癌细胞中RORα表达降低诱导巨噬细胞浸润和M2 极化;目标3.定义RORα在抑制乳腺癌形成和转移中的作用。的 拟议的研究因其固有的科学重要性和转化潜力而具有高度影响力。本研究将 阐明组织极性破坏诱导巨噬细胞的分子机制 渗透/分化。确定RORα在减少ROS产生和抑制NF-κB中的作用 激活可能是一种抑制乳腺癌发展和进展的新策略。