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

项目摘要 衰老对乳房生物学有很大的影响。虽然第一次足月怀孕的早期年龄基本上 减少乳腺癌的发生，即35岁后经历第一次怀孕的妇女 乳汁产量不足，更容易罹患乳腺癌。这表明怀孕的年龄 向乳腺细胞传递明显的细胞和分子扰动，影响整个组织的发育。 然而，年龄和怀孕年龄如何影响控制乳房组织的分子机制尚不清楚。 功能，以及这些变化在多大程度上在哺乳动物中进化保守。 我们的目标是了解衰老如何在某种程度上影响乳腺上皮细胞(MECs)的表观基因组 这会改变细胞分化、组织动态平衡和癌症的发生。我们最近发现，早年 小鼠怀孕的风险会导致微血管内皮细胞的表观基因组和产奶量的持久变化。使用 在可诱导的cMYC过表达小鼠模型中，我们还发现早孕可以阻止癌症 妊娠后微血管内皮细胞中该癌基因下游的启动和转录输出。在本建议书中 我们将定义衰老如何影响这些健壮的表型。 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 妊娠诱发的表观基因组图景。我们假设细胞的变化和环境的变化 怀孕带来的转录调控因子在老年小鼠的乳房组织中会发生变化。第二，我们 做出了一个意想不到的观察，怀孕早期会导致自然的 小鼠乳腺中的杀伤T细胞(NKT)免疫细胞。考虑到衰老被广泛地抑制 免疫系统，我们的目标是加深我们对怀孕年龄或乳房老化的理解 微环境，影响常驻免疫细胞的重新编程，以及它们在癌症启动中的作用。 最后，在这项提议的最后一个目标中，我们将寻求确定衰老如何调节分子状态和 支持妊娠诱发的表观遗传学变化的进化起源。使用系统的方法来 检查怀孕年龄在长(人-鼠)和短(人)乳腺组织中的作用 种群)进化时间尺度，我们的目标是揭示乳房对年龄的表观基因组反应的新方面 上皮组织。 总的来说，拟议的研究将为衰老对乳房的影响提供基本的见解 腺体组织生物学，并携带潜在的发现，可以利用来改善乳房健康在 人类。

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.