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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