Defining the cellular and molecular effects of aging and age of pregnancy on breast tissue homeostasis and cancer initiation

定义衰老和怀孕年龄对乳腺组织稳态和癌症发生的细胞和分子影响

• 批准号: 10417248
• 负责人: Camila dos Santos
• 金额: $ 35.77万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417248
• 关键词: Adaptive Immune System; Address; Age; Age-Years; Aging; Biological Models; Biology; Breast; Breast Epithelial Cells; Cancer Control; Cell Differentiation process; Cells; Cytotoxic T-Lymphocytes; DNA Methylation; Data; Development; Environment; Epigenetic Process; Event; Evolution; Female; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Health; Homeostasis; Hormones; Human; Immune; Immune system; Investigation; Light; Link; Malignant - descriptor; Mammals; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Modality; Modification; Molecular; Mus; Oncogenes; Organism; Organoids; Outcome; Output; Phenotype; Physiology; Population; Predisposition; Pregnancy; Pregnancy Maintenance; Program Development; Publishing; Reporting; Reproduction; Research; Role; Signal Transduction; Time; Tissues; Variant; Woman; Work; age effect; age related; aged; base; c-myc Genes; cancer initiation; epigenome; epigenomics; experience; human model; improved; insight; malignant breast neoplasm; mammary; mammary epithelium; milk production; milk supply; mouse model; novel; overexpression; pregnant; response; transcriptomics; tumor-immune system interactions; tumorigenesis

Project Summary Aging has a strong influence on breast biology. While an early age of first full-term pregnancy substantially reduces breast cancer initiation, women that experience their first pregnancy after 35 years of age experience insufficient milk production, and are more likely to develop breast cancer. This suggest that age of pregnancy delivers distinct cellular and molecular perturbations to breast cells that influence the overall tissue development. Yet, it is unknown how aging and age of pregnancy influences molecular mechanisms that control breast tissue function, and to what extent these changes are evolutionarily conserved across mammals. Our goal is to understand how aging influences the epigenome of mammary epithelial cells (MECs), in a manner that alters cell differentiation, tissue homeostasis, and cancer initiation. We have recently found that an early age of pregnancy in mice leads to enduring changes in the epigenome of MECs and milk production. Using an inducible cMYC overexpressing mouse model, we also found that an early age of pregnancy blocks cancer initiation and the transcriptional output downstream of this oncogene in post-pregnancy MECs. In this proposal we will define how aging influences these robust phenotypes. First, we will use epigenomics and transcriptomics to define how aging influences the establishment of pregnancy-induced epigenomic landscape. We hypothesize that cellular alterations, and changes to the milieu of transcription regulators brought by pregnancy will be altered in mammary tissue from aged mice. Second, we have made an unexpected observation that an early age of pregnancy induces a substantial expansion of Natural Killer T-cell (NKT) immune cells in the mammary gland of mice. Given that aging is known to broadly suppress the immune system, we aim to deepen our understanding on how age of pregnancy, or an aged mammary microenvironment, influences the reprograming of resident immune cells, as well as their role in cancer initiation. Finally, in the last aim of this proposal, we will seek to determine how aging modulates the molecular state and evolutionary origins underpinning pregnancy-induced epigenetic changes. Using systematic approaches to examine the role of the age of pregnancy in the mammary tissue at both long (human-mouse) and short (human population) evolutionary time scales, we aim to reveal novel aspects of epigenomic response to age in the breast epithelium. Collectively, the proposed research will provide fundamental insights into the effects of aging on the mammary gland tissue biology, and carry the potential for discoveries that could be harnessed to improve breast health in humans.

项目概要 衰老对乳房生物学有很大影响。虽然首次足月妊娠的年龄较早 减少乳腺癌的发生，35 岁后第一次怀孕的女性经历过 产奶量不足，更容易患乳腺癌。这表明怀孕年龄 向影响整体组织发育的乳腺细胞提供独特的细胞和分子扰动。 然而，尚不清楚衰老和怀孕年龄如何影响控制乳腺组织的分子机制 功能，以及这些变化在哺乳动物中进化上保守的程度。 我们的目标是了解衰老如何以某种方式影响乳腺上皮细胞（MEC）的表观基因组 改变细胞分化、组织稳态和癌症发生。我们最近发现，从小 小鼠怀孕导致 MEC 表观基因组和产奶量发生持久变化。使用 在诱导性 cMYC 过表达小鼠模型中，我们还发现早孕可以预防癌症 妊娠后 MEC 中该癌基因的起始和转录输出下游。在这个提案中 我们将定义衰老如何影响这些强大的表型。 首先，我们将使用表观基因组学和转录组学来定义衰老如何影响衰老的建立 妊娠引起的表观基因组景观。我们假设细胞的改变和环境的改变 怀孕带来的转录调节因子将在老年小鼠的乳腺组织中发生改变。第二，我们 出人意料地观察到，早孕会导致自然细胞的大量扩张 小鼠乳腺中的杀伤性 T 细胞 (NKT) 免疫细胞。鉴于已知衰老会广泛抑制 免疫系统，我们的目标是加深我们对怀孕年龄或老年乳房如何影响免疫系统的了解 微环境影响常驻免疫细胞的重新编程及其在癌症发生中的作用。 最后，在本提案的最后一个目标中，我们将寻求确定衰老如何调节分子状态和 进化起源支撑着妊娠引起的表观遗传变化。使用系统的方法 检查怀孕年龄在长（人-小鼠）和短（人）乳腺组织中的作用 人口）进化时间尺度，我们的目标是揭示乳房年龄的表观基因组反应的新方面 上皮。 总的来说，拟议的研究将为衰老对乳房的影响提供基本见解 腺组织生物学，并具有可用于改善乳腺健康的发现潜力 人类。