p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator

Authors

Joy M McDaniel
Rhiannon L Morrissey
Denada Dibra
Lalit R Patel
Shunbin Xiong
Yun Zhang
Gilda P Chau
Xiaoping Su
Yuan Qi
Adel K El-Naggar
Guillermina Lozano

Publication Date

8-1-2024

Journal

Cancer Research Communications

Abstract

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/− or MaPR245W/− mammary tumors to MaP−/− tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer.

Keywords

Animals, Female, Humans, Mice, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Mammary Neoplasms, Animal, Mammary Neoplasms, Experimental, Mutation, Mutation, Missense, Transcriptome, Triple Negative Breast Neoplasms, Tumor Suppressor Protein p53

Comments

Supplementary Materials

Data Availability Statement

PMID: 38994678