Abstract
AbstractBothTP53andESR1mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity betweenTP53andESR1mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay betweenTP53andESR1mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features.ESR1mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression inTP53mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences ofTP53andESR1mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity betweenESR1andTP53mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.
Funder
Breast Cancer Research Foundation
Susan G. Komen
U.S. Department of Health & Human Services | NIH | National Cancer Institute
John S. Lazo Cancer Pharmacology Fellowship
U.S. Department of Defense
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Radiology, Nuclear Medicine and imaging,Oncology
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