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Roles of RORalpha in breast cancer development and progression

RORalpha 在乳腺癌发生和进展中的作用

基本信息

批准号：
10199950
负责人：
Ren Xu
金额：
$ 11.29万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199950
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/antagonist insight knock-down loss of function macrophage malignant breast neoplasm mammary metabolomics monocyte multidisciplinary novel novel strategies stable isotope transcriptome tumor tumor microenvironment tumor progression wound

项目摘要

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