# The Role of the Mutant p53-PARP-MCM Pathway in Triple Negative Breast Cancer

> **NIH NIH R01** · HUNTER COLLEGE · 2024 · $328,101

## Abstract

Project Summary:
The Role of the Mutant p53-PARP-MCM Pathway in Triple Negative Breast Cancer
Mutant p53 (mtp53) is found in 80% of triple negative breast cancers (TNBCs). There is a need
to increase understanding of mtp53 signaling in TNBC in order to determine strategies to detect
and treat the disease. TNBCs are more common in African American women than in white
women and therefore the proposed work will benefit all women with TNBC including the AA
over-represented population. This application proposes to determine the biological role of
TNBC-associated gain-of-function oncogenic mtp53 R273H that is associated with PARP1
(herein referred to as PARP) protein, MCM2-7 helicases and replicating DNA. The p53 Arg 273
substituted with His, and other hotspot p53 missense mutant proteins, are well known to
function as oncogenic proteins in TNBCs, but their functions outside of acting as aberrant
transcription co-factors are not clearly understood. The R273H mtp53 is present in high levels
on chromatin in many TNBCs and works as a co-factor to activate the transcription of sterol
biosynthesis genes and chromatin remodeling factors, but incredibly R273H also co-associates
with PARP and MCMs on replicating DNA. Our studies have uncovered this novel replication-
associated pathway and we call it the mtp53-PARP-MCM chromatin axis. Our preliminary and
published data reports that knockdown of mtp53 R273H reduces chromatin associated MCM2-7
and PARP. Knockdown of mtp53 in this setting decreases combined PARP inhibitor (PARPi)
talazoparib plus DNA damaging agent temozolomide-mediated cell death, demonstrating that
mtp53 expression influences the sensitivity of cancer cells to synergistic PARPi plus DNA
damage mediated cell killing. Our preliminary and published data showed nuclear mtp53
R273H co-associates with PARP and MCMs and mtp53 R273H directly associates with EdU at
nascent replication forks. Furthermore, we detected high mtp53 R273H, high PARP protein, and
high PARP enzymatic activity in patient derived xenograft tissue expressing R273H mtp53. We
also detected high co-association of mtp53 and PARP in TNBC in a preliminary tumor
microarray screen as well as through analysis of The Cancer Genome Atlas reverse phase
protein data sets. As a result, we consider understanding the biology of chromatin-associated
mtp53-PARP-MCM complexes on replicating DNA to be an area of inquiry that will have a
sustained long-term influence on our understanding, detection, and treatment choices for TNBC
in diverse populations of women. The mtp53-PARP-MCM axis in TNBC is an innovative
pathway and elucidating the mechanistic relationship of the proteins working together in
replication-associated activities will help us to better understand the disease. Our hypothesis
is that stable mtp53 interacts with replicating DNA during replication stress using amino
acids from its carboxy-terminal regions. As a consequence, the mtp53-PARP-MCM axis is
engaged allowing increased recruitmen...

## Key facts

- **NIH application ID:** 10772009
- **Project number:** 5R01CA239603-05
- **Recipient organization:** HUNTER COLLEGE
- **Principal Investigator:** Jill E. Bargonetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $328,101
- **Award type:** 5
- **Project period:** 2020-02-06 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772009

## Citation

> US National Institutes of Health, RePORTER application 10772009, The Role of the Mutant p53-PARP-MCM Pathway in Triple Negative Breast Cancer (5R01CA239603-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10772009. Licensed CC0.

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