# Targeting ER+ Breast Cancer Through Induced Viral Mimicry

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $441,716

## Abstract

PROJECT SUMMARY
Repetitive elements (REs) compose ~45% of the human genome and are normally transcriptionally silenced in
somatic cells, although the mechanism had remained elusive. Through a high-content RNAi screen, we identified
the largely uncharacterized protein FBXO44 as an essential repressor of REs in breast cancer cells. FBXO44
bound repressive histone H3 lysine 9 trimethylated (H3K9me3) nucleosomes at the replication fork and recruited
H3K9me3 methyltransferase SUV39H1, ubiquitin ligase CRL4RBBP4/7, and histone deacetylase and chromatin-
remodeling complex Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1
inhibition transcriptionally reactivated endogenous retroviruses (ERVs) and retrotransposons (e.g. Alu, LINE-1)
in breast cancer cells, leading to extensive DNA replication stress and stimulation of RIG-I/MDA5-MAVS and
cGAS-STING intracellular antiviral pathways to promote enhanced immunogenicity and decreased
tumorigenicity. In silico analysis revealed the FBXO44/SUV39H1 pathway inversely correlated with DNA
replication stress, antiviral pathways, and cytotoxic T and natural killer (NK) cell infiltration in human breast
tumors. Importantly, FBXO44/SUV39H1 were found dispensable for RE silencing in normal cells and their
inhibition had no effect on H3K9me3 levels, DNA replication stress, or viability, suggesting a therapeutic window.
Our hypothesis is that FBXO44/SUV39H1-mediated RE silencing is an epigenetic vulnerability of breast
cancer cells that could be targeted to inhibit tumor growth/progression and enhance the efficacy of
certain antitumor therapies through the unique mechanism of induced viral mimicry. In this proposal, we
will evaluate 3 potential therapeutic applications of FBXO44/SUV39H1 pathway targeting in the treatment of
estrogen receptor (ER)+ breast cancers based on our preliminary data: 1) prevention of bone metastasis relapse
through stimulation of NK cell recognition and killing of dormant breast cancer cells; 2) enhancement of immune
checkpoint blockade (ICB) therapy through stimulation of IFN signaling and intratumoral infiltration of cytotoxic
T cells; and 3) synergy with PARP inhibitors through induction of DNA replication stress and double-strand
breaks (DSBs) at REs. These studies could lead to the development of a safe and effective therapeutic approach
that selectively induces viral mimicry in ER+ breast cancer cells to prevent bone metastasis relapse and enhance
the efficacy of ICB and PARP inhibitor therapies, undoubtedly leading to a significant reduction in disease
mortality.

## Key facts

- **NIH application ID:** 10416945
- **Project number:** 1R01CA269339-01
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** CHARLES H. SPRUCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,716
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416945

## Citation

> US National Institutes of Health, RePORTER application 10416945, Targeting ER+ Breast Cancer Through Induced Viral Mimicry (1R01CA269339-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10416945. Licensed CC0.

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