Chemoprevention of breast cancer with rexinoids that inhibit obesity-induced metabolic syndrome

使用抑制肥胖引起的代谢综合征的类毒素来化学预防乳腺癌

基本信息

批准号：
9098489
负责人：
Venkatram Reddy Atigadda
金额：
$ 19.18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098489
关键词：
Accounting Address Adipocytes Adipose tissue Adverse effects Affect Aftercare Agonist Animal Feed Animal Model Animals Aromatase Inhibitors Bexarotene Binding Breast Epithelial Cells Calorimetry Candidate Disease Gene Cellular Metabolic Process Chemoprevention Chemopreventive Agent Cholesterol Complex Contralateral Breast Data Development Diet Drug Design Epidemiologic Studies Estrogen receptor negative Estrogen receptor positive FDA approved Fatty acid glycerol esters Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting General Population Genes High Fat Diet High Risk Woman Homeostasis Homo Hyperlipidemia Inflammation Insulin Libraries Life Link Lipids MCF10A cells Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measures Mediating Metabolic Metabolic syndrome Metabolism Modeling Molecular Mouse Mammary Tumor Virus Mus Non-Malignant Nonesterified Fatty Acids Nuclear Receptors Obesity Pathway interactions Patients Pharmaceutical Preparations Population Postmenopause Premalignant Premenopause Prevention Primary Neoplasm Quantum Mechanics RNA RXR Raloxifene Recruitment Activity Retinoic Acid Receptor Retinoids Risk Risk Factors Role Selective Estrogen Receptor Modulators Serum Small Interfering RNA Structure Tamoxifen Testing Time Tissues Titrations Toxic effect Triglycerides Woman base cancer prevention design dimethylbenzanthracene fasting glucose feeding high risk lipid biosynthesis malignant breast neoplasm mouse model mutant novel novel strategies outcome forecast prevent public health relevance receptor screening transcriptome sequencing tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The life-long risk of breast cancer ranges from ~12% in the general population, to over 65% in high-risk women (such as BRCA mutant carriers), emphasizing the need for safe and effective chemoprevention. Currently approved drugs, tamoxifen and raloxifene, prevent only ER-positive (ER+) breast tumors. Thus, the prevention of ER-negative (ER-) cancers remains a major challenge. Rexinoid agonists of RXR nuclear receptors, such as Targretin, prevent both ER+ and ER-cancers in animal chemoprevention models; but they induce severe hyperlipidemia, which limits their use. Using structure-based drug design, we developed a structurally unique group of rexinoids, Class III UAB rexinoids (exemplified by UAB125 andUAB126), with potent chemopreventive efficacy in an ER-mouse model. However, these Class III rexinoids are unique among chemopreventive rexinoids in that they actually lower, rather than elevate, serum lipid levels in treated animals. Moreover, our preliminary data suggest that UAB126 prevents diet-induced obesity and metabolic syndrome, both of which increase the risk of developing breast cancer. Thus, we hypothesize that (1) Class III rexinoids can counteract the tumor-promoting effects of high-fat diet and obesity; and (2) the metabolic actions of these rexinoids may, in part, mediate their chemopreventive activity by directly affecting the metabolic homeostasis of normal and/or (pre)malignant mammary epithelial cells. To address these concepts, chemopreventive activity will be evaluated in an ER-mouse model by assessing rexinoid-induced differences in tumor number, tumor mass, and time to tumor occurrence between animals fed normal or high-fat diet (HFD). These studies will reveal the chemopreventive efficacy of Class III rexinoids in a HFD setting. The molecular mechanisms of rexinoid chemoprevention will be addressed with a three-prong approach: (1) using RNAseq to assess gene expression patterns induced by HFD and/or treatment with Class III rexinoids in distinct tissues (mammary tumors, normal mammary tissue, adipocytes), which will identify potential pathways of rexinoid action; (2) using Isothermal calorimetry to assess rexinoid-induced stabilization of select co-regulator:receptor complexes, which will define specific roles of these rexinoids as agonists/antagonists of distinct RXR heterodimers; and (3) using siRNA screening to identify genes and pathways functionally relevant for the chemopreventive action of Class III rexinoids. Integration of these findings will lay the basis for future studies of the causal links between obesity, metabolic syndrome, and initiation and progression of breast cancer.

描述（由申请人提供）：乳腺癌的终生风险范围从普通人群的约 12% 到高危女性（如 BRCA 突变携带者）的 65% 以上，强调需要安全有效的化学预防目前批准的药物他莫昔芬和雷洛昔芬只能预防 ER 阳性 (ER+) 乳腺肿瘤，因此，预防 ER 阴性 (ER-) 癌症仍然是一个重大挑战。 RXR 核受体的 Rexinoid 激动剂（例如 Targretin）可在动物化学预防模型中预防 ER+ 和 ER-癌症；但它们会诱发严重的高脂血症，这限制了它们的使用。 III 类 UAB rexinoids（以 UAB125 和 UAB126 为例），在 ER 小鼠模型中具有有效的化学预防功效。 III 类类毒素在化学预防性类毒素中是独一无二的，因为它们实际上会降低而不是升高动物的血清脂质水平。此外，我们的初步数据表明 UAB126 可以预防饮食引起的肥胖和代谢综合征，这两种疾病都会增加发生治疗的风险。因此，我们认为 (1) III 类类毒素可以抵消高脂肪饮食和肥胖的促肿瘤作用；(2) 这些类毒素的代谢作用可能部分地：通过直接影响正常和/或恶性乳腺上皮细胞的代谢稳态来介导其化学预防活性为了解决这些概念，将通过评估rexinoid诱导的肿瘤数量、肿瘤的差异在ER小鼠模型中评估化学预防活性。这些研究将揭示 III 类 rexinoids 在 HFD 环境中的化学预防功效。 Rexinoids化学预防的研究将通过三管齐下的方法来解决：（1）使用RNAseq来评估不同组织（乳腺肿瘤、正常乳腺组织、脂肪细胞）中HFD和/或III类rexinoids治疗诱导的基因表达模式，这将确定 rexinoid 作用的潜在途径；(2) 使用等温量热法评估 rexinoid 诱导的选定协同调节器：受体复合物的稳定性，这将确定这些复合物的具体作用rexinoids 作为不同 RXR 异二聚体的激动剂/拮抗剂；(3) 使用 siRNA 筛选来鉴定与 III 类 rexinoids 化学预防作用功能相关的基因和途径，这些发现的整合将为以下研究奠定基础。肥胖、代谢综合征与乳腺癌发生和进展之间因果关系的未来研究。