# Identifying Cooperating Mutations Contributing to Disease Progression in Mutant p53-Driven Breast Cancer

> **NIH NIH F31** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $29,854

## Abstract

PROJECT SUMMARY ABSTRACT
Breast cancer progression is not a linear process; an in situ tumor does not always progress into an invasive
lesion. It is difficult to predict which tumors will remain localized, and which will likely spread to other tissues.
This problem is exacerbated because multiple genetic drivers can induce breast cancer. One such gene is p53;
about 30% of breast cancers involve a missense mutation in the p53 DNA binding domain. The most common
hot spot mutation in human cancers is at residue R248, orthologous to the mouse R245 residue. This mutation,
often R245W (substituting arginine for tryptophan), induces invasive ductal carcinoma. Our laboratory maintains
a mouse cohort with an Adenovirus-packaged Cre recombinase-induced conditional p53R245W mutation, with a
median latency period of about 18 months until invasive carcinoma (IC) development. Pathological analysis of
mammary tissue identified IC along with ductal carcinoma in situ (DCIS), allowing us to characterize the full
spectrum of mutant p53-driven breast cancer progression. This project aims to define how mutant p53 drives
DCIS development and progression into IC. Human sequencing data shows that breast cancer displays robust
intertumoral heterogeneity, thus we hypothesize that mutant p53 drives initial tumorigenesis, and
cooperates with additional mutations to drive the development from DCIS to IC. In Aim 1, we will
characterize mutant p53-dependent DCIS progression in vivo. We will define a timeline of DCIS development
and progression to IC, as well as exome sequencing and RNA sequencing DCIS and IC lesions to identify
mutations and genes/pathways necessary for invasion. In Aim 2, we will investigate the mechanisms contributing
to breast carcinoma disease progression, and functionally characterize cooperating lesions identified in Aim 1.
This project will elucidate how an initial p53 mutation can induce DCIS development and progression to IC.
Cooperating mutations will be characterized to distinguish those associated with a DCIS lesion that will remain
localized from a DCIS lesion that is likely to progress to invasion. We aim to identify mutations cooperating with
mutant p53 to drive invasion, to potentially elucidate strategies to stratify treatment for DCIS lesions, based on
their genetic alterations. The Lozano laboratory at MD Anderson is the perfect environment for me to complete
my project and learn mouse modeling and cancer genetics. During my graduate training, I will meet with my
advisory committee as a group biannually, and individually as needed. I will write a review and 2 first-author
publications, present my work regularly, and attend one national/international conference annually. I will have
the opportunity to interact with world-class scientists at MD Anderson (including my Sponsor), and have access
to state-of-the-art technology and core facilities. I will also participate in Genetics Department seminars, including
weekly Research Exchange and Blaff...

## Key facts

- **NIH application ID:** 10413028
- **Project number:** 5F31CA246917-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Rhiannon Morrissey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $29,854
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413028

## Citation

> US National Institutes of Health, RePORTER application 10413028, Identifying Cooperating Mutations Contributing to Disease Progression in Mutant p53-Driven Breast Cancer (5F31CA246917-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10413028. Licensed CC0.

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