Network-based approach elucidates critical genes in BRCA subtypes and chemotherapy response in Triple Negative Breast Cancer

Breast cancers exhibit substantial transcriptional heterogeneity, posing a significant challenge to the prediction of treatment response and prognostication of outcomes. Especially, translation of TNBC subtypes to the clinic remains a work in progress, in part because of a lack of clear transcriptional signatures distinguishing the subtypes. Our recent network-based approach, PathExt, demonstrates that global transcriptional changes in a disease context are likely mediated by a small number of key genes, and these mediators may better reflect functional or translationally relevant heterogeneity. We apply PathExt to 1059 BRCA tumors and 112 healthy control samples across 4 subtypes to identify frequent, key-mediator genes in each BRCA subtype. Compared to conventional differential expression analysis, PathExt-identified genes (1) exhibit greater concordance across tumors, revealing shared as well as BRCA subtype-specific biological processes, (2) better recapitulate BRCA-associated genes in multiple benchmarks, and (3) exhibit greater dependency scores in BRCA subtype-specific cancer cell lines. Single cell transcriptomes of BRCA subtype tumors reveal a subtype-specific distribution of PathExt-identified genes in multiple cell types from the tumor microenvironment. Application of PathExt to a TNBC chemotherapy response dataset identified TNBC subtype-specific key genes and biological processes associated with resistance. We described putative drugs that target top novel genes potentially mediating drug resistance. Overall, PathExt applied to breast cancer refines previous views of gene expression heterogeneity and identifies potential mediators of TNBC subtypes, including potential therapeutic targets.