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 这项提议的目标是了解怀孕过渡对分子和细胞的影响。 乳腺上皮细胞状态与肿瘤发生大量的流行病学研究发现， 怀孕会改变患乳腺癌的风险。这些研究一直表明，足月怀孕 25岁以前患乳腺癌的人一生中罹患乳腺癌的几率降低三分之一。当一个 怀孕的保护作用已在癌症啮齿动物模型中得到验证，其潜在的分子基础是 这种影响目前还不清楚。 我们发现，怀孕会导致微血管内皮细胞表观基因组和增强子图谱的持续变化。 使用可诱导的c-myc小鼠模型，我们还发现肿瘤发生和转录输出 这种癌基因的下游在妊娠后的微血管内皮细胞中减少。在这项提案中，我们将调查 这些强健表型背后的分子基础。我们将使用表观基因组学、体外、体内和生化 方法确定c-myc的转录功能是如何受妊娠调节的。我们假设c- 在这个系统中，MYC与辅因子和特定顺式调控元件的相互作用发生了变化。 我们还将研究特定的染色质调节因子如何对妊娠介导的表观基因组重排做出贡献。 这些努力将建立在我们最近的数据基础上，该数据表明EZH2支持怀孕后的 野生型老鼠。总而言之，这项研究将提供对乳腺细胞生物学的基本见解 并携带潜在的发现，可以被利用来开发预防性治疗， 调节人类患乳腺癌的风险。