# Mechanisms by which mutant p53 drives metastatic Triple Negative Breast Cancer

> **NIH NIH F32** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $67,446

## Abstract

PROJECT SUMMARY/ABSTRACT
This research project aims to investigate in vivo gain-of-function (GOF) mechanisms of the p53R245W hotspot
mutation involved in initiation and progression of metastatic triple negative breast cancer. The genetic drivers
of metastatic breast cancer, particularly triple negative breast cancer, are poorly understood. Approximately
54% of invasive breast cancers harbor a missense mutation in TP53, with the p53R248W hotspot mutation
having the greatest association with poor survival. The Lozano lab has generated a somatic mouse model for
p53R245W (murine counterpart to human p53R248W). The conditional allele expresses wild type p53, which
converts to mutant p53 upon Cre recombinase activation. Ductal injection of adenovirus-Cre into the mouse
mammary gland allows mutant p53 expression in a few cells surrounded by a normal stroma and immune
system. Studies in our somatic breast cancer model indicates p53R245W mice give rise to a broad spectrum of
breast tumors (n=25): Esr1-Pgr-Erbb2-(triple negative, 30.8%); Esr1-Pgr- Erbb2+(Her2-enriched, 38.4%) or
Esr1/Pgr+Erbb2+ (luminal B, 30.8%) and 58% of these tumors become metastatic. The TNBC tumors generated
in this model are of interest because 88% of human TNBCs harbor a p53 alteration. We hypothesize that
p53R245W gain of function mechanisms cooperate with other genetic events leading to metastatic TNBC.
We will use an integrated genomics approach to investigate how p53R245W contributes to breast cancer
metastasis by (1) ChIP-seq and RNA-seq to discover transcriptional co-factor(s) and target genes mediating
mutant p53 GOF and (2) isolation of circulating tumor cells followed by single cell copy number and RNA-seq
analysis to explore cell survival and metastasis. There is a knowledge gap of the genomic landscape associated
with mutant p53 and its role in the development of metastatic TNBC. Data from the proposed studies will provide
a better understanding of the GOF mechanism of the p53R245W hotspot mutation and how it contributes to the
evolution of metastatic TNBC.
The proposed research is sponsored by Dr. Guillermina Lozano, an expert in p53 biology and genetically
engineered mouse models, with extensive experience investigating the role of p53 and its pathway components
in cancer. This research plan is co-sponsored by Dr. Nicholas Navin, an expert and early developer of single-
cell sequencing, with experience implementing single-cell genomics to study the evolution of human breast
cancers. The PI will have an Advisory Committee of additional experts including Dr. Michelle Barton and Dr.
Jeffrey Rosen to provide mentoring during the award period. The primary objective of the training plan is to
provide the PI with experience in cancer genetics, genomics, and mouse models to prepare her for a career as
an independent investigator in breast cancer biology.

## Key facts

- **NIH application ID:** 9881177
- **Project number:** 5F32CA232463-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Joy Marie McDaniel
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881177

## Citation

> US National Institutes of Health, RePORTER application 9881177, Mechanisms by which mutant p53 drives metastatic Triple Negative Breast Cancer (5F32CA232463-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881177. Licensed CC0.

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