ABSTRACT
Breast cancers (BRCA) exhibit substantial transcriptional heterogeneity, posing a significant clinical challenge. The global transcriptional changes in a disease context, however, are likely mediated by few key genes which reflect disease etiology better than the differentially expressed genes (DEGs). We apply our network-based tool PathExt to 1,059 BRCA tumors across 4 subtypes to identify key mediator genes in each subtype. Compared to conventional differential expression analysis, PathExt-identified genes exhibit greater concordance across tumors, revealing shared and subtype-specific biological processes; better recapitulate BRCA-associated genes in multiple benchmarks, and are more essential in BRCA subtype-specific cell lines. Single-cell transcriptomic analysis reveals 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 subtype-specific key genes and biological processes associated with resistance. We described putative drugs that target key genes potentially mediating drug resistance.