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

Abstract

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.

Highly heterogeneous-related genes of triple-negative breast cancer: potential diagnostic and prognostic biomarkers

“…Gene expression microarray datasets were obtained from the GEO database ( https://www.ncbi.nlm.nih.gov/geo/ ) according to the following requirements: (1) dataset was mRNA expression profile data; (2) the information of the platform annotation was accessible; (3) the expression data of microarray had been published. Therefore, the datasets including GSE115275 [ 33 ] and GSE62931 [ 34 ] were downloaded by GEO query package in R software (version 3.6.1, https://www.r-project.org ). Meanwhile, mRNA sequencing data of 1247 samples of breast cancer and normal breast tissue were acquired from the TCGA database ( http://portal.gdc.cancer.gov/ ).…”

BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

“…We first characterized BAD protein and phosphoprotein levels during mammary gland development in the wild-type animal. Serines 112, 136, and 155 are coordinately phosphorylated 26 and we used either anti-PS112 or anti-PS136 antibodies that were validated for western blot or immunofluorescence, to monitor phosphorylated BAD (P-BAD). Total BAD protein levels are similar in pubertal, nulliparous adult and involuting glands and elevated in pregnant glands (Fig.…”

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

“…2h, i). Since in this TMA the overall survival data of the patients had been reported 29 , we stratified the patients based on the levels of TROLL-2 and TROLL-3 and found that high levels of either lncRNA correlated with reduced overall survival of these breast cancer patients ( Fig. 2c, d).…”

“…The Moffitt tissue microarrays (TMAs) used in this study consisted of: (i) 68 breast cancer samples comprising 43 triple negative and 25 non-triple negative breast cancers (TMA-5) 29 ; and (ii) 100 melanoma samples and 6 control cases (TMA-4). The formalin-fixed and paraffin-embedded biopsies were used to produce 0.6 mm cores, which were assembled into the two TMAs by the Tissue Core Facility at the H. Lee Moffitt Cancer Center & Research Institute under delegated ethical authority of the Moffitt Research Ethics Committee with written informed consent from contributing patients.…”