Expression of the BAD pathway is a marker of triple-negative status and poor outcome

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.National Cancer Institute, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1R21 CA-181617-01]; Total Cancer Care Initiative; Collaborative Data Services Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]; DeBartolo Family; Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]; Cancer Informatics Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]; Analytic Microscopy Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu