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

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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.