Environmental factors and compounds affecting the genomic stability in haploinsufficient BRCA1 cells.

影响单倍体 BRCA1 细胞基因组稳定性的环境因素和化合物。

基本信息

批准号：
10735532
负责人：
Jeannine Gerhardt
金额：
$ 111.4万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2023-09-07 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735532
关键词：
Acceleration Affect Alleles Apoptotic Awareness BRCA1 gene Biological Breast Cancer Risk Factor Breast Epithelial Cells Cancer Etiology Cells Chemopreventive Agent Clinical Cosmetics DNA DNA Damage DNA Repair DNA Sequence Alteration DNA biosynthesis DNA lesion DNA replication fork Data Defect Deletion Mutation Development Environmental Pollutants Environmental Risk Factor Estrogen receptor negative Exhibits Exposure to Fertility Food Genes Genetic Genome Genome Stability Genomic Instability Genomics Germ-Line Mutation Health Incidence Induced Mutation Inherited Knowledge Link Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mammospheres Mutagenesis Mutation Nutritional Oncogenes Pathway interactions Patient Self-Report Patients Pharmaceutical Preparations Point Mutation Prevention strategy Preventive Quality of life Reporting Risk Site Somatic Mutation Stress Testing Toxic Environmental Substances Toxin Tumor Suppressor Genes Tumor Suppressor Proteins cancer cell cancer initiation cancer risk carcinogenesis carcinogenicity dietary environment related cancer epidemiology study experimental study genetic testing high risk neoplastic cell novel preservation prevent repaired tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Germline mutations in the BRCA1 gene are associated with higher risk of carcinogenesis. This high risk is linked to an increased mutation rate and loss of the second unaffected BRCA allele (loss of heterozygosity, LOH). It is well accepted that both environmental and genetic factors contribute to cancer etiology in BRCA1 carriers. However, knowledge about the biological mechanisms and environmental factors that influence the genomic stability in haploinsufficient BRCA1 cells is still lacking. In addition, dietary agents that avert mutagenesis and cancer, in particular estrogen receptor (ER)-negative cancer development in BRCA1 carriers are not known. It was reported that haploinsufficient BRCA1 cells obtained from BRCA1 carriers exhibit deficient repair of stalled replication. Our preliminary results show an increase replication defects and a rise in DNA breaks in haploinsufficient BRCA1 cells exposed to novel environmental factors, which were not described so far to cause genomic instability, in BRCA1 carrier cells. In addition, our preliminary data reveal a new dietary agent that can reduce DNA damage and increase the genomic stability in haploinsufficient BRCA1 cells. This proposal will investigate in aim 1 and 2 how environmental factors cause DNA replication and repair defects that lead to mutations and cancer cell development in haploinsufficient BRCA1 breast epithelial cells. And in aim 3 this study will identify novel dietary agents that are able to prevent these defects and reduce mutagenesis in haploinsufficient ER-negative BRCA1 cells. In summary, the experiments in this proposal will detect toxins that affect the genomic stability and new chemopreventive agents that avert defects and mutagenesis in haploinsufficient BRCA1 breast epithelial cells. Identification of chemopreventive agents, which avoid mutagenesis and LOH in haploinsufficient BRCA1 cells, would be extremely important for BRCA1 carriers.

项目概要/摘要 BRCA1 基因的种系突变与较高的致癌风险相关。这种高风险是与突变率增加和第二个未受影响的 BRCA 等位基因丢失（杂合性丢失，哦）。人们普遍认为环境和遗传因素都会影响 BRCA1 的癌症病因载体。然而，关于影响的生物机制和环境因素的知识单倍体不足的 BRCA1 细胞的基因组稳定性仍然缺乏。此外，饮食制剂可以避免突变和癌症，特别是 BRCA1 携带者中雌激素受体 (ER) 阴性的癌症发展不知道。据报道，从 BRCA1 携带者获得的单倍体不足的 BRCA1 细胞表现出对停滞复制的修复不足。我们的初步结果显示复制缺陷增加并且单倍体不足的 BRCA1 细胞暴露于新的环境因素时发生 DNA 断裂，而这些环境因素并没有迄今为止，已被描述会在 BRCA1 携带细胞中引起基因组不稳定。此外，我们的初步数据显示新的膳食制剂可以减少 DNA 损伤并提高单倍体 BRCA1 不足的基因组稳定性细胞。该提案将在目标 1 和 2 中研究环境因素如何导致 DNA 复制和修复导致单倍体 BRCA1 乳腺上皮细胞突变和癌细胞发育的缺陷。在目标 3 中，这项研究将确定能够预防这些缺陷并减少单倍体不足的 ER 阴性 BRCA1 细胞中的诱变。总之，本提案中的实验将检测影响基因组稳定性的毒素和避免缺陷的新化学预防剂单倍体 BRCA1 乳腺上皮细胞不足的突变。化学预防剂的鉴定，其中避免单倍体不足的 BRCA1 细胞发生突变和 LOH，对于 BRCA1 极其重要载体。