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

• 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
• 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

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.

摘要/项目摘要 该提案的目标是了解怀孕期间的转变如何影响分子和细胞 乳腺上皮细胞的状态和肿瘤发生。大量流行病学研究发现 怀孕会改变患乳腺癌的风险。这些研究一致表明，足月妊娠 25 岁之前的乳腺癌与终生乳腺癌发病率降低三分之一相关。虽然一个 怀孕的保护作用已在啮齿动物癌症模型中得到验证，这是癌症的潜在分子基础 这种影响仍不清楚。 我们发现怀孕会导致 MEC 的表观基因组和增强子景观发生持续变化。 使用诱导型 c-MYC 小鼠模型，我们还发现肿瘤发生和转录输出 该癌基因的下游在怀孕后 MEC 中减少。在本提案中，我们将调查 这些强大的表型背后的分子基础。我们将使用表观基因组学、离体、体内和生物化学 确定妊娠如何调节 c-MYC 转录功能的方法。我们假设 c- MYC 与辅因子和特定顺式调控元件的相互作用在该系统中发生了改变。 我们还将研究特定的染色质调节因子如何促进妊娠介导的表观基因组重连。 这些努力将建立在我们最近的数据基础上，这些数据表明 EZH2 支持妊娠后表观基因组 野生型小鼠。总的来说，这项研究将为乳腺细胞生物学提供基本见解 腺体并具有发现的潜力，可用于开发预防性治疗方法 调节人类乳腺癌风险。