# NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $390,917

## Abstract

Project Summary: While previously unrecognized, it is now documented that having delivered a child within
10 years is an independent predictor of early onset breast cancer and poor outcomes. These cancers, based
largely on work from our labs, is now referred to as postpartum breast cancer (PPBC), and represents a
significant clinical problem. Every year in the US alone, ~15,000 young women (accounting for ~50% of all
young women’s breast cancer cases) are diagnosed during the high risk, postpartum period. Research in our
lab has advanced the hypothesis that weaning-induced mammary gland involution is the driver of increased
incidence and metastasis in PPBC patients. During the transitory window of weaning-induced involution, the
normal involuting mammary gland is skewed towards a pro-tumor microenvironment, as it exhibits increased
lymphangiogenesis, fibroblast activation, and extracellular matrix deposition; as well as enrichment for myeloid
derived suppressor cells (MDSC), M2-skewed macrophages, and Th-17, Th-2 and Treg skewed T cells
compared to nulliparous glands. These discoveries support our hypothesis that sub-clinical, non-life
threatening disease progresses to overtly invasive cancer during weaning-induced involution. In multiple
murine models, we confirm that the tissue microenvironment of the involuting gland increases mammary tumor
incidence and progression. Further, we demonstrate that ibuprofen (IBU) treatment targeted to the involution
window blocks >50% of these tumors from emerging, depending on model. Further, of those tumors that do
emerge, progression to metastatic disease is suppressed. One mechanism by which IBU appears to inhibit
PPBC is through anti-tumor immunity, as IBU increases the number of cytotoxic T cells, consistent with
increased immune surveillance. Importantly, we find the ability of IBU to restore the adaptive arm of the
immune system occurs in the absence of adverse host autoimmune reactions and does not impact the ability
of dams to successfully nurse their young in subsequent pregnancies. These findings support clinical utility of
IBU in the setting of a PPBC prevention trial. Our studies also identify opportunities to improve efficacy, and
vitamin D (Vit D) is proposed based on its anti-tumor and anti-inflammatory activity, and its safety and
particular relevance in postpartum women, who are at high risk for VitD deficiency. Here we propose to 1)
investigate the efficacy of IBU treatment in combination with vitamin D, in rodent models of PPBC with
improved human relevance, 2) identify the mechanism by which IBU +/- VitD mitigates the pro-tumorigenic
microenvironment of the involuting gland with the goal of identifying additional involution-specific targets; and
3) translate our rodent studies defining the ‘immune composition of the “at risk” involuting mammary gland to
women, by defining the immune milieu in the normal human breast across reproductive states. Only through
understanding how the normal, invo...

## Key facts

- **NIH application ID:** 10113546
- **Project number:** 5R01CA169175-08
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Pepper J Schedin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,917
- **Award type:** 5
- **Project period:** 2013-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113546

## Citation

> US National Institutes of Health, RePORTER application 10113546, NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention (5R01CA169175-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10113546. Licensed CC0.

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