# Targeting Iron-Sulfur Cluster Biosynthesis for the Treatment of Basal-Like Breast Cancer

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $50,520

## Abstract

Project Summary/Abstract
 Breast cancer accounts for the second most cancer-related deaths in U.S. women despite the availability of
improved treatment options and increased screening. A particularly aggressive subtype that represents a
disproportionate number of these mortality cases is basal-like breast cancer (BLBC). This subtype frequently
relapses and has a propensity to metastasize. Moreover, no directed therapies exist for BLBC. Hence, to
improve outcomes for patients with this subtype, the identification of novel vulnerabilities in BLBC that would
allow for the design and development of directed treatments is required. Strikingly, we find that BLBC cell
lines, but not luminal cell lines, exhibit a severe sensitivity to suppression of iron-sulfur cluster (ISC)
biosynthesis, a pathway that supports the function of at least 48 proteins involved in cellular processes such as
energy metabolism, iron homeostasis, and DNA replication and repair. Moreover, suppression of NFS1, a key
enzyme in the ISC biosynthetic pathway, prevents basal-like breast cancer metastasis to the lung. Thus, the
identification of which downstream ISC containing proteins drive this sensitivity promises to elucidate pathway
vulnerabilities in BLBC that could potentially lead to a targeted therapy for this subtype with a poor prognosis
and limited treatment options. The proposed work in this fellowship will identify differentially required ISC
containing proteins in BLBC and then will validate them using in vitro and xenograft models to investigate the
effects of suppressing the proteins on tumor formation, growth, and metastasis. Validated targets will then be
tested in the same models for synergy with current BLBC treatments. Preliminary data suggests that induction
of genomic instability upon ISC biosynthesis suppression contributes to the proliferation defects observed in
BLBC cell lines. Further experiments demonstrate that DNA Polymerase ε (POLE), the leading strand
replicative polymerase, is one such differentially required protein. We hypothesize that BLBC is highly
sensitive to POLE suppression due to a DNA repair defect in this tumor type that renders POLE activity critical
for genomic integrity. To evaluate this hypothesis, complementary and independent approaches that analyze
DNA damage signaling pathways, examine replication propagation and origin firing, and genetically dissect the
role of POLE subunits will be employed. These approaches will provide a stringent characterization of the role
of POLE in DNA damage repair pathways in BLBC. Collectively, our proposed work will identify and
characterize ISC pathway vulnerabilities in BLBC from which novel targeted therapies could be developed.

## Key facts

- **NIH application ID:** 9997835
- **Project number:** 5F30CA228202-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Vladislav Sviderskiy
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997835

## Citation

> US National Institutes of Health, RePORTER application 9997835, Targeting Iron-Sulfur Cluster Biosynthesis for the Treatment of Basal-Like Breast Cancer (5F30CA228202-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997835. Licensed CC0.

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