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

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

Blog Article

Abstract Both TP53 and ESR1 mutations 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 between TP53 and ESR1 mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown.Here, we explored the interplay between TP53 and ESR1 mutations 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 Driver Route Planning Method Based on Accident Risk Cost Prediction their clinical and distinct mutational features.

ESR1 mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression in TP53 mutant 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 HOW A RESEARCH ARTICLE INTRUDUCTION STRUCTURED? THE ANALYSIS OF SWALES MODEL (CARS) ON ENGLISH RESEARCH ARTICLE INTRODUCTIONS rare cases with co-occurrences of TP53 and ESR1 mutations 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 between ESR1 and TP53 mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.