# Targeting the senescence-associated secretory phenotype as an adjuvant therapy to prevent breast cancer progression

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $435,827

## Abstract

ABSTRACT
Most breast cancer deaths result from the emergence of metastatic spread of tumor cells. While the use of
cytotoxic cancer therapies allows for the near complete eradication of malignant breast cells, relapse occurs in
many cases. Surprisingly, these relapsed cancer cells often display more aggressive phenotypes than the
primary tumors they derive from, in agreement with the recent demonstration that exposure to chemotherapy
can favor invasiveness and metastatic features in resistant cancer cells. Such effects are likely driven by both
tumor intrinsic and tumor extrinsic changes in response to therapy-induced stress. Identifying approaches to
blunt these changes during exposure to chemotherapy could provide a therapeutic avenue to prevent the
emergence of aggressive tumor cells following anti-cancer treatment.
Sustained exposure to genotoxic stress can drive cells into a stable cell cycle exit known as cellular senescence.
Exposure to chemotherapy represents a well-recognized pro-senescent stimulus. In addition to a stable cell cycle
exit, senescent cells are characterized by their ability to secrete a discrete set of pro-inflammatory cytokines and
chemokines, referred to as the SASP (Senescence Associated Secretory Phenotype). Importantly, we and
others have demonstrated that the presence of SASP is sufficient to promote invasive and migratory phenotypes
in breast cancer cells. Therefore, we propose that chemotherapy promotes the acquisition of aggressive traits in
cancer cells at least in part through exposure to the SASP secreted by host and cancer cells rendered senescent
as a result of the treatment.
We will test the overarching hypothesis that targeting the chemotherapy-induced SASP or its downstream targets
could serve as an adjuvant therapy to blunt the emergence of aggressive breast tumors after treatment.
Specifically, we will: identify the cell population responsible for SASP production in vivo after exposure to
chemotherapy, and assess the impact of inhibiting IL-1α, a master regulator of the SASP, on chemotherapy-
induced emergence of aggressive breast cancer cells in mouse models (aim 1). We will also ascertain whether
expression of lipocalin 2 (LCN2), a known pro-metastatic factor in breast cancer which we found strongly
upregulated in breast cancer cells exposed to the SASP, correlates with exposure to chemotherapy in samples
from human breast cancer patients. Furthermore, we will test whether LCN2 inhibition blunts the SASP-induced
migratory and invasive phenotype in vitro, and mitigates the occurrence of metastases following chemotherapy
treatment in vivo (aim 2). The long-term goal of this research is to identify novel therapeutic targets to prevent
the resurgence of aggressive breast cancer.

## Key facts

- **NIH application ID:** 10049419
- **Project number:** 1R21CA246416-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Gregory David
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,827
- **Award type:** 1
- **Project period:** 2020-07-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049419

## Citation

> US National Institutes of Health, RePORTER application 10049419, Targeting the senescence-associated secretory phenotype as an adjuvant therapy to prevent breast cancer progression (1R21CA246416-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10049419. Licensed CC0.

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