# Targeting Senescence and the senescent secretome to impact breast cancer formation

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $395,973

## Abstract

Project Summary
Senescence and the senescence associated secretory phenotype (SASP) have long been implicated in driving
tumorigenesis. However, the pro-tumorigenic mechanism(s) of senescence are still not fully understood, pointing
to a need for better model systems to study the role of senescence in tumorigenesis. We recognized that a breast
cancer model that used irradiation of cleared mammary fat pads followed by implantation of syngeneic Comma-
D cells could be an ideal system to study senescence effects on tumorigenesis. Implantation of Comma-D alone
does not result in outgrowth of tumors, but requires pre-irradiation of the gland for tumorigenesis. Similarly,
treatment of the mammary fat pad with chemicals prior to implantation can also drive tumorigenesis. Both these
types of treatments are also known to induce senescence, and indeed we found that irradiation induces massive
senescence in the tissue. Thus, we hypothesize that tumorigenesis in this model system relies on induction of
senescence to drive tumor formation, and that targeting the senescent cells or specific SASP factors will impair
tumorigenesis. We propose to study this model system further to show that tumorigenesis requires induction of
senescence in two specific aims. In the first aim, we will treat irradiated animals with senolytic drugs to remove
senescent cells prior to implantation of SCp2 and other mammary cells, and compare tumor incidence in this
group to a control arm that are treated with vehicle alone. Our preliminary data indicates that targeted removal
of senescent cells with navitoclax blocks tumor formation. Extension of our studies will establish that senescence
can drive early tumorigenesis in multiple models. In the second aim, we will examine how senescence drives
pre-neoplastic cell growth, survival, and differentiation in vivo using multiplex immunofluorescence. We will
perform RNAseq to identify SASP factors that are upregulated in response to irradiation. We will test these
factors for their ability to enhance growth of SCp2 and human mammary epithelial cells (HMECs) in vitro. SASP
factors that enhance growth and survival of these cells will be selected for targeting to determine their role in
tumor formation. We will use small molecule inhibitors of receptors or interfering antibodies for SASP factors to
determine how blocking these putative growth promoting factors impacts tumor formation. Successful completion
of these studies will establish whether tumorigenesis in a luminal mammary cell implantation system is driven by
senescence, will identify mechanisms by which senescence drives tumorigenesis, and will demonstrate the
ability of senolytics or small molecule inhibitors targeting SASP factors to impair tumorigenesis. These represent
the first steps in gaining mechanistic understanding of the role of senescence in early mammary tumorigenesis,
with a long term goal of developing anti-senescence approaches for the prevention or treatment of human b...

## Key facts

- **NIH application ID:** 10942512
- **Project number:** 1R21CA286419-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** James Korkola
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,973
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942512

## Citation

> US National Institutes of Health, RePORTER application 10942512, Targeting Senescence and the senescent secretome to impact breast cancer formation (1R21CA286419-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10942512. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*