Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer

• DOI: 10.1038/s41523-022-00426-w
• Publication Date: 2022-05-10T10:03:22Z
• Authors: Zheqi Li; Nicole S. Spoelstra; Matthew J. Sikora; Sharon B. Sams; Anthony Elias; Jennifer K. Richer; Adrian V. Lee; Steffi Oesterreich
• Keywords: Estrogen receptor alpha

Abstract Both TP53 and ESR1 mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) their distinct roles cancer tumorigenesis progression are well appreciated. Recent clinical studies discovered mutual exclusivity between cancers; however, mechanisms underlying this intriguing observation remain largely understudied unknown. Here, we explored the interplay using publicly available experimental data sets. We first confirmed robust mutational six independent cohorts with 1,056 ER+ MBC samples found that broadly applies to all tumors regardless of features. mutant do not exhibit differential p53 pathway activity, whereas identified attenuated ER activity expression tumors, driven by a p53-associated E2 response gene signature. Further, 81% these genes either direct targets wild-type (WT) p53-regulated transactivation or microRNAs, representing bimodal suppression. Lastly, analyzed very rare cases co-occurrences simultaneous presence was also associated reduced activity. In addition, dual showed higher levels total PD-L1 macrophages. summary, our study utilized multiple sources explore mechanism mutations, providing further insights testable hypotheses molecular two pivotal MBC.