Triple-negative breast cancer (TNBC) is considered as the most aggressive cancer subtype of the breast, and its intrinsic heterogeneity impedes elucidation of dysregulated molecular pathways and subsequently obstructs the development of targeted therapies. In this study we performed proteomics mass spectrometry of human breast cancer cell lines, resulting in the identification of two TNBC subclasses, basal A and basal B, with distinct proteomic profiles and associated molecular mechanisms. Within this subclasses, we found especially kinases and proteases to display unique expression pattern, indicating prominent functional roles in orchestrating discrete molecular functions. Focusing on those two protein classes, we used a comprehensive and advanced computational workflow to further interrogate subclass specific protein interactions and their associated perturbations, revealing deregulated pathways and possible targets for each TNBC subclass. While we found cell cycle, apoptosis and keratinization to be responsible for tumorigenesis in basal A subclass via NF-kB and WNT signaling. We identified kinase AXL and TGFBR1/2, and proteases FAP and MMP2/14, which play a central role in invasion and metastasis, to regulate EMT and TGF signaling in the generally more aggressive basal B subclass.
These observations highlight a distinct involvement of proteases and kinases in a subclass-specific regulation of tumorigenesis within TNBC. Thus, it has to be emphasized, that such proteins have to be exploited for targeted therapy in a subclass-specific manner, rather than for TNBC in general.