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Blockade of cMYC oncogenic function by pregnancy-induced alterations and remodeling of the mammary gland

通过妊娠引起的乳腺改变和重塑来阻断 cMYC 致癌功能

基本信息

批准号：
10734182
负责人：
Camila dos Santos
金额：
$ 51万
依托单位：
COLD SPRING HARBOR LABORATORY
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：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734182
关键词：
Acute Affect Age BRCA1 gene Biochemical Birth Breast Breast Adenocarcinoma Breast Cancer Risk Factor Breast Epithelial Cells Cancer Model Cells Cellular biology Chromatin DNA Methylation Data Development EZH2 gene Enhancers Epigenetic Process Event Exposure to Female Future Gene Expression Genetic Transcription Goals Hormones Human Hyperplasia Incidence Knowledge Lesion Life Link Machine Learning Malignant - descriptor Malignant Neoplasms Mammary Tumorigenesis Mammary gland Mediating Methods Modeling Molecular Morphogenesis Mus Nulliparity Oncogenes Oncogenic Organoids Outcome Output Pathway interactions Phenotype Physiology Pregnancy Preventive treatment Property Regulatory Element Reproduction Research Risk Rodent Rodent Model Role System Testing Therapeutic Intervention Tissues Transcriptional Activation Transcriptional Regulation Transgenic Animals Transgenic Mice Wild Type Mouse Woman Work c-myc Genes cancer subtypes cell type chromatin remodeling cofactor epidemiology study epigenome epigenomics genetic approach in vivo insight malignant breast neoplasm mammary mouse model novel overexpression parous post pregnancy pregnant prepregnancy prevent protective effect response small molecule inhibitor tumor tumorigenesis

项目摘要

Abstract/Project Summary The goal of this proposal is to understand how transitions through pregnancy influence the molecular and cellular state of mammary epithelial cells and oncogenesis. Numerous epidemiological studies have found that pregnancy alters the risk of breast cancer. These studies have shown consistently that a full-term pregnancy prior to the age of 25 is associated with a one-third decrease in the life-time incidence of breast cancer. While a protective effect of pregnancy has been validated in rodent models of cancer, the underlying molecular basis for this effect remains unclear. We have found that pregnancy leads to persistent changes in the epigenome and enhancer landscape of MECs. Using an inducible c-MYC mouse model, we also find that oncogenesis and the transcriptional output downstream of this oncogene are reduced in post-pregnancy MECs. In this proposal we will investigate the molecular basis underlying these robust phenotypes. We will use epigenomics, ex vivo, in vivo and biochemical methods to define how the transcriptional function of c-MYC is modulated by pregnancy. We hypothesize that c- MYC interactions with cofactors and with specific cis-regulatory elements are altered in this system. We will also study how specific chromatin regulators contribute to pregnancy-mediated epigenomic rewiring. These efforts will build upon our recent data suggesting that EZH2 supports the post-pregnancy epigenome in wild-type mice. Collectively, this research will provide fundamental insights into the cell biology of the mammary gland and carry the potential for discoveries that could be harnessed to develop preventative treatments that modulate breast cancer risk in humans.

抽象/项目总结