Deciphering intra-tumoral roles of TGFβ isoforms in triple negative breast cancer (TNBC)

The heterogeneity in triple-negative breast cancer (TNBC) is one of the classical characteristics that contribute to its aggressiveness. The absence of oestrogen, progesterone, and low expression of HER2 receptors making chemotherapy is the only therapeutic mainstay in TNBC. Displaying high sensitivity to chemotherapy, disease recurrence is often a common event in TNBC patients too. Transforming Growth Factor β (TGFβ) is a growth factor ligand that releases cytokines highly reported in TNBC progression and response to drugs. The distinctive roles of molecular mechanisms in TNBC development between TGFβ isoforms are not fully established. Therefore, this study aimed to elucidate the cryptic intra-tumoral transcriptomic characteristics of each isoform (TGFβ1, TGFβ2, TGFβ3) from publicly available TNBC GEO datasets (GSE58812, GSE76124, GSE83937, and GSE95700). A total of 486 TNBC samples were stratified to represent TGFβ1-high versus TGFβ1-low, TGFβ2-high versus TGFβ2-low, and TGFβ3-high versus TGFβ3-low. The differential gene expression analysis showed distinct genes being expressed downstream to each isoform (TGFβ1-high–573 genes; TGFβ2-high–41 genes; TGFβ3-high–36). Interestingly, gene ontology and pathway analysis exhibited similar enrichment of the metabolic, cellular polarity, and Rap1 signalling pathways, all of which play critical roles in cancer progression through interplay crosstalk, represented in all isoforms. Some of the highlighted gene signatures were shown to possess clinical relevance in TNBC samples; each represents either protective or poorer prognostic effects, delineating potential targetable genes with diagnostic and prognostic values. This data offers a platform to explore further the roles of each isoform for better stratifying TNBC patients for treatment invention strategies.