# Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $513,768

## Abstract

PROJECT SUMMARY
African American (AA) women are disproportionately affected by triple negative breast cancer (TNBC), a highly
heterogeneous and aggressive subtype of breast cancer. We found that AA patients with TNBC have a higher
risk of death from the disease than their European American (EA) counterparts, which is independent of their
sociodemographic and clinical factors. Notably, this TNBC disparity is more obvious in patients receiving
chemotherapy. However, the molecular mechanisms driving differential tumor response to chemotherapy and
the consequent prognostic disparities in AA vs. EA TNBCs remains unknown. Most chemotherapy agents exert
their cytotoxic effects through the induction of deadly DNA double-strand breaks (DSBs) that are repaired by
two major mechanisms: error-free homologous recombination (HR) and error-prone non-homologous end-
joining (NHEJ). Genomic stability and survival of tumor cells upon genotoxic treatments are known to depend
on HR. Our pilot study showed that AA TNBCs tend to have higher expression of HR-related proteins and
lower expression of NHEJ-related proteins compared with EA TNBCs. The AAA+ ATPase VCP has been
suggested to influence the choice of DSB repair pathways in favor of HR as opposed to NHEJ. We recently
reported that Ser784 phosphorylation of VCP is required for DNA damage repair and intra-tumor pSer784-VCP
levels predict poor survival in TNBC patients, particularly those receiving chemotherapy. Our pilot data also
showed that both total VCP protein and DNA damage-induced pSer784-VCP levels are higher in AA vs. EA
TNBC samples. Based on these data, we hypothesize that AA TNBCs, relative to EA TNBCs, are intrinsically
more capable of repairing chemotherapy-induced DSBs by HR as opposed to NHEJ due to differential
expression levels and functionality of DSB repair factors including pSer784-VCP, which underlies their worse
clinical outcomes. We propose three specific aims. First, we will confirm racial differences in protein expression
of HR and NHEJ factors in tumor tissues obtained from two large cohorts of TNBC patients and examine their
contribution to survival disparities. Second, we will experimentally compare HR and NHEJ efficiencies between
AA and EA TNBC cell line and patient-derived mouse xenograft (PDX) models, and correlate the racial
differences in DSB repair pathway choice and genotoxic chemotherapy effects. Third, we will examine the
ability of pSer784-VCP to regulate DSB repair pathway choice and genotoxic chemotherapy effects in AA TNBC
models. The proposed study will greatly improve our understanding of the molecular mechanisms underlying
racial disparities in TNBC treatment response and outcomes. The results will also help create new disparity
intervention strategies by establishing pSer784-VCP as a novel predictive biomarker and sensitizing target for
genotoxic chemotherapy treatments in AA TNBCs.
.

## Key facts

- **NIH application ID:** 10347836
- **Project number:** 1R01CA266041-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ying Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,768
- **Award type:** 1
- **Project period:** 2022-02-03 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347836

## Citation

> US National Institutes of Health, RePORTER application 10347836, Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes (1R01CA266041-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10347836. Licensed CC0.

---

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