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

Unlabelled: 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.

Significance: Our findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. NR5A2 may be an important therapeutic target in hard-to-treat breast cancers such as endocrine-resistant tumors and metastatic triple-negative breast cancers harboring TP53 missense mutations.