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。虽然第一次足月妊娠的年龄很小， 减少乳腺癌的发生，35岁后首次怀孕的女性 产奶量不足，更容易患乳腺癌。这表明怀孕年龄 将不同的细胞和分子扰动传递到影响整体组织发育的乳腺细胞。 然而，年龄和怀孕年龄如何影响控制乳腺组织的分子机制尚不清楚。 功能，以及这些变化在哺乳动物中进化保守的程度。 我们的目标是了解衰老如何影响乳腺上皮细胞（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， 小鼠怀孕的持续时间导致MEC表观基因组和产奶量的持久变化。使用 在诱导型cMYC过表达小鼠模型中，我们还发现， 启动和转录输出下游的这种癌基因在怀孕后MEC。本提案中 我们将定义衰老如何影响这些强健的表型。 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 怀孕引起的表观基因组景观。我们假设细胞的改变，以及环境的改变 在老年小鼠乳腺组织中，妊娠带来的转录调节因子的表达将发生改变。二是 我做了一个意想不到的观察，早期怀孕诱导了大量的自然扩张， 小鼠乳腺中的杀伤T细胞（NKT）免疫细胞。考虑到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的理解，或一个年老的乳房 微环境，影响常驻免疫细胞的重编程，以及它们在癌症起始中的作用。 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， 进化起源支持怀孕引起的表观遗传变化。采用系统方法， 在长（人-小鼠）和短（人）的乳腺组织中检查怀孕年龄的作用 人口）进化的时间尺度，我们的目标是揭示新的方面的表观基因组反应的年龄在乳房 上皮 总的来说，拟议的研究将为衰老对乳腺癌的影响提供基本的见解。 腺体组织生物学，并携带发现的潜力，可以利用，以改善乳房健康， 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.