# Regulation of Type I Interferon Pro-tumor Effects in Breast Cancer

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2022 · $362,043

## Abstract

Project Summary/Abstract
Adjuvant radiotherapy or chemotherapy is a standard treatment for breast cancer patients after surgical resection
of cancer. However, cancer cells commonly develop therapeutic resistance. A crucial factor that decides whether
a tumor relapses or responds to these cancer therapies is the dual role of interferon (IFN) in promoting or
counteracting cancer progression, respectively. A set of IFN-stimulated genes (ISGs), the so-called “IFN-related
DNA damage resistance signature” (IRDS), was recently implicated in resistance to irradiation and
chemotherapy in different types of cancers, including breast cancer. While irradiation and some of chemotherapy
drugs cause DNA damage in cancer cells, IFN1 induces expression of IRDS that mediates DNA damage
resistance to treatments. Therefore, in theory, inhibiting the IFN1 pathway could restore therapeutic sensitivity.
However, indiscriminate suppression of IFN1 signaling could also constrain its anti-tumor effects, which will not
provide the desired clinical efficacy to patients. Inhibiting the IRDS-mediated pro-tumor activities but reserving
the IFN1-induced anti-tumor effects could be a favorable strategy to provide major benefit to patients. To this
end, understanding how the IRDS is regulated and how it protects cancer cells against therapies is urgent and
important. AT-rich interaction domain 4B (ARID4B) belongs to the ARID family and is a chromatin remodeling
protein. Our preliminary data demonstrate that ARID4B is highly expressed in human breast cancer and its high
expression is associated with poor clinical outcomes in breast cancer patients. Knockout of ARID4B in breast
cancer cell lines and mouse models compromised tumorigenesis. In addition, ablation of ARID4B reduced DNA
damage repair and increased sensitivity to irradiation and DNA-damaging drugs in breast cancer cells.
Mechanistically, ARID4B is required for IFN1-mediated activation of the STAT1-IRDS axis and regulates
PARylation/dePARylation in breast cancer cells. A central hypothesis for this proposal is: The IFN1 pro-tumor
effects are determined by ARID4B, because ARID4B is crucial for activation of the IFN1-STAT1-IRDS signaling
pathway that regulates PARylation/dePARylation-dependent DNA damage response to promote breast cancer
progression and therapeutic resistance to irradiation and DNA-damaging drugs. The hypothesis will be tested
by three specific aims: Aim 1. Determine the role of ARID4B on regulation of PARylation/dePARylation-
dependent DNA damage response to promote the IFN1-IRDS pro-tumor effects. Aim 2. Identify the mechanism
by which ARID4B regulates the IFN-STAT1-IRDS pathway. Aim 3. Preclinical analyses of ARID4B impact on
breast cancer resistance to irradiation and DNA-damaging drugs. This study is innovative because it uncovers
ARID4B as the specific determinant of IFN pro-tumor effects. This study is significant because analyses of
ARID4B function and its regulatory pathway could lead to new therap...

## Key facts

- **NIH application ID:** 10450823
- **Project number:** 5R01CA255996-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Mei-Yi Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,043
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-01-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450823

## Citation

> US National Institutes of Health, RePORTER application 10450823, Regulation of Type I Interferon Pro-tumor Effects in Breast Cancer (5R01CA255996-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450823. Licensed CC0.

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