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SELENOF is a Novel Tumor Suppressor and a New Target to Overcome Racial Disparity in Breast Cancer.

SELENOF 是一种新型肿瘤抑制剂，也是克服乳腺癌种族差异的新靶点。

基本信息

批准号：
10735662
负责人：
Irida Kastrati
金额：
$ 46.58万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-11 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735662
关键词：
3&apos Untranslated Regions Acceleration Address Affect Affinity African American African American population Automobile Driving Binding Biological Factors Biological Markers Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Epithelial Cells Caucasians Cell Death Cell Death Induction Cell Line Cell Survival Cells Clinic Clinical DNA Data Dependence Development Disease Disease Progression Enzymes Eukaryotic Initiation Factors Frequencies Genetic Polymorphism Genome Immunocompetent In Vitro Incidence Inositol Knockout Mice Mammary Neoplasms Mammary Tumorigenesis Measures Messenger RNA Modeling Mutation Oncogenic Outcome Oxidoreductase Pathway interactions Patient-Focused Outcomes Patients Phenocopy Phenotype Phosphotransferases Pre-Clinical Model Predisposition Proliferating Proteins RNA Race Regulation Reporter Repression Ribonucleases Risk SNP genotyping Sampling Selenocysteine Single Nucleotide Polymorphism Stains Testing Therapeutic Therapeutic Intervention Translational Repression Translations Treatment Efficacy Tumor Suppressor Proteins Variant Woman Work XBP1 gene Xenograft Model Xenograft procedure aggressive breast cancer breast tumorigenesis cancer genome candidate marker cell growth dimethylbenzanthracene disparity gap effective therapy in vitro Assay in vivo in vivo Model inhibitor mRNA Expression malignant breast neoplasm metaplastic cell transformation mortality mouse model novel novel therapeutic intervention overexpression personalized medicine pharmacologic preclinical study racial disparity response selenoprotein therapeutic target three dimensional cell culture transcription factor treatment response tumor tumor DNA tumor growth tumor progression tumorigenesis

项目摘要

Project Summary / Abstract This proposal addresses the challenge of closing the racial disparity gap in breast cancer mortality by identifying a contributing biological factor and developing therapeutic strategies to overcome its impact. The selenoprotein, SELENOF, was recently identified as a new tumor suppressor in breast cancer. The broad hypothesis is that lower SELENOF levels in African American patients contribute to the racial disparity in breast cancer mortality by driving tumor progression and poor patient outcome. Therefore, therapeutic strategies to mitigate its loss are needed to help close the disparity gap. The scientific premise for the hypothesis is based on the following: 1) the genomes of breast tumors from African Americans have a 5-10 fold higher frequency of SELENOF single nucleotide polymorphisms (SNPs), which account for lower SELENOF protein levels, 2) SELENOF mRNA expression is significantly lower in breast tumors from African American patients compared to Caucasians, and lower SELENOF levels predict shorter survival in these patients, 3) loss of SELENOF in normal breast epithelial cells resulted in increased proliferation and abrogated cell death, features of cellular transformation, and 4) overexpression of SELENOF in breast cancer cells induced cell death, blocked proliferation and survival, enhanced response to therapies, and inhibited tumor growth in vivo. The eukaryotic initiation factor 4a3 (eIF4a3) was identified as a translational repressor of SELENOF. The SELENOF locus SNPs are predicted to enhance eIF4a3’s binding affinity resulting in stronger repression of SELENOF translation. Preliminary data showed that pharmacologic inhibition of eIF4a3 results in increased SELENOF protein levels and reduced breast cancer cell viability in a SELENOF-dependent manner. Loss of SELENOF also resulted in hyperactivation of the kinase/RNase inositol-requiring enzyme 1 (IRE1), a master regulator of the unfolded protein response. This rendered cells highly susceptible to IRE1 inhibition, thus identifying a new vulnerability in these cells. Four aims are proposed: 1) Determine the mechanisms underlying SELENOF-induced cell fate in breast cancer, 2) Determine whether loss of SELENOF drives tumorigenesis by using African American derived xenografts and a murine model of breast cancer, 3) Determine the impact of SNPs on the regulation of SELENOF translation by eIF4a3, and 4) Determine whether eIF4a3 overexpression and the SNPs contribute to reduced SELENOF tumor levels and poor outcome in African American breast cancer patients. Our work will establish SELENOF as a new target to reduce racial disparity in breast cancer, and thus support the development of SELENOF-based therapies. In the clinic, SELENOF’s SNPs and levels can also serve as candidate biomarkers to identify African American patients at risk of aggressive disease. The distinct therapeutic strategies investigated here are likely to result in novel and more effective personalized medicine and may help close the disparity gap.

项目摘要/摘要这项提案旨在解决缩小乳腺癌死亡率种族差异差距的挑战一个促成生物因素，并制定治疗策略，以克服其影响。硒蛋白， SELENOF，最近被确定为乳腺癌的一种新的肿瘤抑制因子。广义的假设是非裔美国患者中SELENOF水平较低是乳腺癌死亡率种族差异的原因通过推动肿瘤进展和糟糕的患者结局。因此，减轻其损失的治疗策略是需要帮助缩小差距。这一假设的科学前提是基于以下几点：1) 非裔美国人的乳腺肿瘤基因组中单个SELENOF的频率高出5-10倍核苷酸多态(SNPs)，这解释了SELENOF蛋白水平较低，2)SELENOF mRNA 与高加索人相比，非洲裔美国人患者的乳腺肿瘤中的表达显著降低，并且 SELENOF水平较低预示着这些患者的存活时间较短，3)正常乳腺上皮中SELENOF的丢失导致细胞增殖增加和细胞死亡，细胞转化的特征，以及4) SELENOF在乳腺癌细胞中的过表达导致细胞死亡，抑制增殖和存活，增强对治疗的反应，并抑制体内肿瘤的生长。真核细胞起始因子4a3(EIF4a3) 被鉴定为SELENOF的翻译抑制因子。SELENOF基因座SNPs预计会增强 EIF4a3‘与S结合亲和力较强，对SELENOF翻译有较强的抑制作用。初步数据显示，药物抑制eIF4a3导致SELENOF蛋白水平升高和乳腺癌细胞减少以依赖于SELENOF的方式生存。SELENOF的丢失也导致了细胞的过度激活激酶/核糖核酸酶肌醇需要酶1(IRE1)，是未折叠蛋白反应的主要调节因子。这使细胞对IRE1抑制高度敏感，从而在这些细胞中发现了一个新的脆弱性。四个目标建议：1)确定SELENOF在乳腺癌中诱导细胞命运的机制，2) 通过使用非裔美国人来源的异种移植和一种小鼠乳腺癌模型，3)确定SNPs对SELENOF翻译调控的影响 EIF4a3，以及4)确定eIF4a3过表达和SNPs是否有助于降低肿瘤的SELENOF 非裔美国人乳腺癌患者的水平和不良预后。我们的工作将把SELENOF建立为一个新的旨在减少乳腺癌的种族差异，从而支持以SELENOF为基础的发展治疗。在临床上，SELENOF的SNPs和水平也可以作为识别非洲人的候选生物标志物美国患者有患侵袭性疾病的风险。这里研究的不同的治疗策略很可能从而产生新颖和更有效的个性化医疗，并可能有助于缩小差距。