Crosstalk of RNA methylation writers defines tumor microenvironment and alisertib resistance in breast cancer.

Abstract

The five major RNA methylation modifications (m6A, m1A, m6Am, m5C, and m7G) exert biological roles in tumorigenicity and immune response, mediated mainly by "writer" enzymes. Here, the prognostic values of the "writer" enzymes and the TCP1 role in drug resistance in breast cancer (BC) were explored for further therapeutic strategies. We comprehensively characterized clinical, molecular, and genetic features of subtypes by consensus clustering. RNA methylation modification "Writers" and related genes_risk (RMW_risk) model for BC was constructed via a machine learning approach. Moreover, we performed a systematical analysis for characteristics of the tumor microenvironment (TME), alisertib sensitivity, and immunotherapy response. A series of experiments in vitro were carried out to assess the association of TCP1 with drug resistance. One "writer" (RBM15B) and two related genes (TCP1 and ANKRD36) were identified for prognostic model construction, validated by GSE1456, GSE7390, and GSE20685 cohorts and our follow-up data. Based on the patterns of the genes related to prognosis, patients were classified into RMW_risk-high and RMW_risk-low subtypes. Lower RMW_Score was associated with better overall survival and the infiltration of immune cells such as memory B cells. Further analysis revealed that RMW_Score presented potential values in predicting drug sensitivity and response for chemo- and immunotherapy. In addition, TCP1 was confirmed to promote BC alisertib-resistant cell proliferation and migration in vitro. RMW_Score could function as a robust biomarker for predicting BC patient survival and therapeutic benefits. This research revealed a potential TCP1 role regarding alisertib resistance in BC, providing new sights into more effective therapeutic plans.