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[https://doi.org/10.1158/2767-9764.CRC-24-0128](https://doi.org/10.1158/2767-9764.CRC-24-0128)  OPEN ACCESS  \np53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator  \nJoy M. McDaniel1, Rhiannon L. Morrissey1,2, Denada Dibra1, Lalit R. Patel1, Shunbin Xiong1, Yun Zhang1,3, Gilda P. Chau1, Xiaoping Su4, Yuan Qi4, Adel K. El-Naggar5, and Guillermina Lozano1  \n􀀶  \nABSTRACT  \nAggressive 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 cellspecific 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 cancerassociated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants.  \nMeta-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. Coimmunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2 . These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer.  \nSignificance: 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.  \nIntroduction  \nBreast cancer comprises four subtypes: luminal A, luminal B, HER2-enriched, and basal-like breast cancer ( 1, 2) . Luminal breast cancers are driven by estrogen receptor (ER) and/or progesterone receptor (PR) . HER2-enriched breast cancers are driven by amplification and constitutive signaling of HER2 . Basal-like breast cancers are often termed triple-negative breast cancer (TNBC) owing to the lack of expression of ER, PR, and HER2 .  \n1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas. 3Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas. 4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.  \nCorresponding Author: Guillermina Lozano, Department of Genetics, The University of Texas Anderson Cancer Center, 1515 Holcombe Boulevard Unit 1010,  \nHouston, TX 77030. E-mail: [gglozano@mdanderson.org](gglozano@mdanderson.org)  \n[doi:](doi: 10.1158/2767-9764)[ 10.1158/2767-9764](doi: 10.1158/2767-9764) .CRC-24-0128  \nThis open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4. 0) license.  \n©2024 The Authors; Published by the American Association for Cancer Research  \nTNBCs are often metastatic and chemoresistant. Development of antihormonal and anti-HER2 therapies has revolutionized breast cancer treatment ( 1–8) . However, there is a need to develop targeted therapies for aggressive breast cancers.  \nA molecular driver associated with aggressive breast cancer is the mutation of TP53 . Recent studies show that TP53 mutations are the most frequent alteration in metastatic breast","cbCaijDFJOq5X5GR","https://ap.wps.com/l/cbCaijDFJOq5X5GR","pdf",26946698,17,"English","# Abstract\n# Introduction\n## Breast cancer subtypes and TP53 alterations\n## Functions of TP53 and mutant p53 mechanisms","[{\"question\":\"What experimental model was used to study TP53 hotspot mutations in breast cancer?\",\"answer\":\"A somatic mouse model was created with mammary epithelial cell-specific expression of Trp53 mutations, producing primary mammary tumors that reflected human molecular subtypes and included metastases.\"},{\"question\":\"What did transcriptomic analyses reveal when comparing tumors driven by p53R172H or p53R245W to control tumors?\",\"answer\":\"They showed differences in cancer-associated pathways activated in both p53 mutants and identified Nr5a2 as a novel transcriptional mediator of distinct pathways in the p53 mutants.\"},{\"question\":\"How is Nr5a2 connected to mutant p53 transcriptional activity?\",\"answer\":\"In vitro assays show mutant p53 upregulates target genes enriched for Nr5a2 response elements, and coimmunoprecipitation indicates p53R172H and p53R245W interact with Nr5a2.\"}]","p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator | PDF",1790003399,43]