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

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2024 · $357,683

## Abstract

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.

## Key facts

- **NIH application ID:** 10848383
- **Project number:** 5R01AG069727-05
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Camila dos Santos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,683
- **Award type:** 5
- **Project period:** 2020-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848383

## Citation

> US National Institutes of Health, RePORTER application 10848383, Defining the cellular and molecular effects of aging and age of pregnancy on breast tissue homeostasis and cancer initiation (5R01AG069727-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848383. Licensed CC0.

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