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。

• 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
• 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' 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

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 该提案解决了通过识别乳腺癌死亡率缩小种族差异差距的挑战 一个促成生物学因素和制定治疗策略来克服其影响。硒蛋白， Selenof最近被确定为乳腺癌的新肿瘤抑制剂。广泛的假设是 非裔美国人患者的硒水平降低导致乳腺癌死亡率的种族差异 通过推动肿瘤进展和患者预后不良。因此，减轻损失的治疗策略是 需要帮助缩小差异差距。该假设的科学前提是基于以下基础：1） 来自非裔美国人的乳腺肿瘤的基因组具有5-10倍的单身频率 核苷酸多态性（SNP），该核苷酸含量较低 与高加索人相比，非裔美国人患者的乳腺肿瘤的表达明显降低， 较低的Selenof水平预测这些患者的生存时间较短，3）正常乳腺上皮中的硒丧失 细胞导致增殖增加和废除细胞死亡，细胞转化的特征，4） 乳腺癌细胞中硒的过表达诱导细胞死亡，阻塞和存活， 增强对疗法的反应，并抑制体内肿瘤的生长。真核开始因子4A3（EIF4A3） 被确定为Selenof的翻译表示。预计Selenof基因座SNP会增强 EIF4A3的结合亲和力导致更强的Selenof翻译表示。初步数据显示 EIF4A3的药理学抑制导致硒蛋白水平升高和乳腺癌细胞降低 以依赖硒的方式生存能力。损失也导致了 激酶/rNase肌醇酶1（IRE1）是展开蛋白反应的主要调节剂。这 渲染的细胞高度容易受到IRE1抑制作用，从而确定了这些细胞中的新脆弱性。四个目标 提出：1）确定乳腺癌中硒诱导的细胞命运的机制，2） 确定Selenof的损失是否使用非裔美国人衍生的Xenographicts和A驱动肿瘤发生 乳腺癌的鼠模型，3）确定SNP对Selenof翻译的影响 EIF4A3和4）确定EIF4A3的过表达和SNP是否有助于减少硒 非裔美国乳腺癌患者的水平和不良结果。我们的工作将确立新的 降低乳腺癌种族差异的目标，从而支持基于Selenof的发展 疗法。在诊所中，Selenof的SNP和水平也可以作为候选生物标志物来识别非洲 有侵略性疾病风险的美国患者。这里研究的独特理论策略可能是 导致新颖，更有效的个性化医学，并可能有助于缩小差异差距。