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Core B

核心B

基本信息

批准号：
10225393
负责人：
Douglas Yee
金额：
$ 25.09万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225393
关键词：
Adjuvant Advanced Development Alleles Animal Model Animals Antiviral Agents Aromatase Inhibition Benign Biological Models Breast Breast Cancer Model Breeding CDK4 gene Cell Cycle Inhibition Cells Chemicals Clinical Clinical Data Communities Copy Number Polymorphism Cytosine deaminase DNA Development Disease Drug resistance Ensure Enterobacteria phage P1 Cre recombinase Enzymes Estrogen Receptors Estrogen receptor positive Estrogens Evolution FDA approved Family Family member Genes Genetic Genetically Engineered Mouse Genomics Goals Heterogeneity Human Image Immunocompetent Introns Malignant Neoplasms Mammals Mammary Neoplasms Modeling Mus Mutagenesis Mutate Mutation NIH 3T3 Cells Neoplasm Metastasis Nuclear Outcome Pharmaceutical Preparations Phenotype Preclinical Testing Primates Process Proteins Publishing RNA analysis Recurrence Reporting Research Personnel Resistance Rodent Role Scientist Services Source Study models Survival Rate System Tamoxifen Testing Therapeutic Time Tissues Transgenic Organisms Work Xenograft Model anticancer research breast cancer survival clinical translation deprivation design driver mutation effective therapy exome sequencing experimental study hormone therapy improved in vivo in vivo Model inhibitor/antagonist innovation insight mRNA Expression malignant breast neoplasm malignant phenotype mammary mouse model mutant overexpression prevent programs resistance mechanism success therapy development transcriptome sequencing tumor

项目摘要

CORE B – MURINE MODELS ABSTRACT Accumulated mutations are often responsible for malignant phenotypes and the development of therapy resistance in estrogen receptor (ER)-positive breast cancer. We have shown that the APOBEC family of DNA cytosine deaminases is an important source of mutation in breast cancer and particularly in ER-positive disease. One family member, APOBEC3B (A3B), is overexpressed and associated with aggressive phenotypes, manifesting as early disease recurrence and decreased clinical benefit from tamoxifen. We have corroborated these clinical data in a xenograft model in which A3B depletion increases and overexpression decreases benefit from tamoxifen over time. Because mice lack an equivalent to the human A3B enzyme, and because animal models will be vital for the long-term goal of providing more effective treatments for breast tumors driven by the APOBEC mutational process, Core B will develop animal models for use by the Program team, its collaborators, and the greater cancer research community. This goal will be achieved through 2 specific aims. Aim 1 will build on our published and preliminary results and advance the development of ER- positive xenograft models for studies on resistance to estrogen deprivation (modeling aromatase inhibition), cell cycle inhibition (CDK4/6 inhibition), and selective estrogen receptor degraders. Aim 2 will advance the development of genetically engineered mouse models with a Cre-inducible A3B minigene by determining the impact of mammary-specific expression of this enzyme in existing genetic backgrounds predisposed to mammary tumors. The most robust A3B-driven models from Aims 1 and 2 will be used to test candidate A3B inhibitors derived from pan-Program efforts led by Projects 2 & 3 and Cores C & D. We expect Core B models to have a high impact by providing our Program team, its collaborators, and the greater cancer research community with robust animal models to interrogate the APOBEC mutation process in vivo, which will be essential for clinical translation and ultimately improving breast cancer survival rates.

核心b -小鼠模型