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The Age-Dependence and Cell-Specificity of Breast Cancer Driven by Mutant p53

p53突变体驱动乳腺癌的年龄依赖性和细胞特异性

基本信息

批准号：
10331816
负责人：
Yun Zhang
金额：
$ 15.3万
依托单位：
TEXAS SOUTHERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331816
关键词：
Adenoviruses Age Alleles Animals Arginine Biodiversity Biological Markers Breast Cancer Model Breast Cancer Patient Cancer Etiology Cells Cessation of life Clinical Codon Nucleotides Cytokeratin Data Dependence Development Diagnosis Diagnostic Disease Elderly Enterobacteria phage P1 Cre recombinase Epithelial Exhibits Female Future Genes Genomics Growth Histologic Histology Human Incidence Injections Investigation Lead Mammary Duct Mammary Neoplasms Mediating Molecular Mus Mutation Myoepithelial Neoplasm Metastasis Patients Pilot Projects Prognosis Proteins Publishing Recording of previous events Recurrence Role Specificity TP53 gene Testing The Cancer Genome Atlas Therapeutic Studies Tryptophan Tumor Subtype Tumor Suppressor Genes Woman age related anticancer research breast cancer diagnosis cancer diagnosis cancer therapy epithelial stem cell exome sequencing improved insight malignant breast neoplasm mammary mammary epithelium molecular subtypes mouse model mutant personalized medicine personalized therapeutic progenitor promoter public database response stem cells tool tumor tumorigenesis young woman

项目摘要

PROJECT SUMMARY Breast cancer is an age-related disease, with higher incidence in elder women and worse prognosis in younger women. Most breast tumors are of epithelial origin. The mammary epithelium consists of an outer basal myoepithelial layer of cells and an inner luminal cell layer. Studies have described the existence of cytokeratin protein 5 (K5) marked bipotent progenitors giving rise to both basal and luminal cells, and cytokeratin protein 8 (K8) marked unipotent progenitors that produce luminal cells only. Surprisingly, despite the long history of breast cancer research, how age impacts breast cancer, and whether and how breast tumors initiated from K5 or K8 positive (K5+ or K8+) progenitors exhibit intrinsic differences remain unclear. Answering these questions may provide new avenues for improved diagnostics and personalized therapeutics that could prolong the lives of patients. The most frequent genetic alterations in breast cancer occur in the tumor suppressor p53, with arginine 248 being the top mutational hotspot. The newly published conditional p53wm-R245W mouse allele, which allows conversion of wild type p53 to p53R245W (corresponding to human p53 arginine to tryptophan mutation at codon 248) in response to Cre recombinase, is a potentially valuable tool for studying the age-dependence and cell-specificity of breast cancer driven by mutant p53. As a prelude for future mechanistic and therapeutic studies, this pilot project will utilize the p53wm-R245W allele to model breast cancer and compare mouse mammary tumors initiated at different ages or from different cellular origins, which are hypothesized to exhibit differences at the histological, molecular or genomic levels. This hypothesis will be tested in three specific aims. The first aim is to compare p53R245W mutant driven mammary tumors initiated in young and old mice. Adenoviruses expressing Cre (Ad-Cre), will be injected into the mammary ducts of 2 months- or 10 months old female p53wm-R245W/+ mice. Tumor incidence, latency and growth rate, animal survival, metastasis, and the spectra of histological and molecular subtypes of tumors will be compared between mice injected with Ad-Cre at the respective ages. The second aim is to compare p53R245W driven mammary tumors initiated from either K5+ or K8+ progenitor cells. p53wm-R245W/+ female mice will receive mammary intraductal injection of adenoviruses AdK5-Cre or AdK8-Cre that express Cre led by the K5 or K8 promoter, respectively. The same parameters as described in Aim 1 will be compared between the mice receiving AdK5-Cre or AdK8-Cre. The last aim is to investigate the age-dependence and cell-specificity of mammary tumors at the genomic level. Whole-exome sequencing (WES) will be performed on tumors produced in Aims 1 and 2. Genes with recurrent alterations will be compared between mammary tumors initiated from the 2 months- and 10 months old mice, as well as between tumors initiated from the K5+ or K8+ progenitor cells. The WES data will also be compared to the human breast cancer sequencing data.

项目总结