Molecular portraits revealing the heterogeneity of breast tumor subtypes defined using immunohistochemistry markers

Abstract

Breast cancer is highly heterogeneous. The subtypes defined using immunohistochemistry markers and gene expression profilings (GEP) are related but not equivalent, with inter-connections under investigated. Our previous study revealed a set of differentially expressed genes (diff-genes), containing 1015 mRNAs and 69 miRNAs, which characterize the immunohistochemistry-defined breast tumor subtypes at the GEP level. However, they may convey redundant information due to the large amount of genes included. By reducing the dimension of the diff-genes, we identified 119 mRNAs and 20 miRNAs best explaining breast tumor heterogeneity with the most succinct number of genes found using hierarchical clustering and nearest-to-center principle. The final signature panel contains 119 mRNAs, whose superiority over diff-genes was replicated in two independent public datasets. The comparison of our signature with two pioneering signatures, the Sorlie's signature and PAM50, suggests a novel marker, FOXA1, in breast cancer classification. Subtype-specific feature genes are reported to characterize each immunohistochemistry-defined subgroup. Pathway and network analysis reveal the critical roles of Notch signalings in [ER+|PR+]HER2- and cell cycle in [ER+|PR+]HER2+ tumors. Our study reveals the primary differences among the four immunohistochemistry-defined breast tumors at the mRNA and miRNA levels, and proposes a novel signature for breast tumor subtyping given GEP data.