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

Bernadette M Boac,Alex Lopez,Hannah Park,Hatem Soliman,Atif Siddique,Forough Abbasi,Yin Xiong,Johnathan M Lancaster,C Robertson Mcclung ,Susmitha Apuri,Daryoush Saeed-Vafa,Sharon E Robertson,Anthony M Magliocco,Anders Berglund ,Weihong Sun,Brendon Henry,Sarah Todd ,M Juliana Pena,Roohi Ismail‐Khan ,Mingda Han,Douglas C Marchion

doi:10.1038/s41598-019-53695-0

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.

Highlights

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment
principal component analysis (PCA) modelling of the BAD pathway gene expression signature (BPGES) in a gene expression dataset, comprised of 106 breast cancer patient samples (53 non-TNBC and 53 TNBC), indicated that a high BPGES score was associated with breast cancers displaying the triple-negative phenotype, with a mean BPGES score of −1.7 ± 0.24 for non-TNBC and 1.7 ± 0.19 for TNBC
As the TNBC group contained a significantly higher percentage of grade 3 tumours, we evaluated whether the BPGES was associated with disease grade

Summary

Introduction

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. 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. 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. PolyADP-ribose polymerase inhibitors have shown some efficacy, the effectiveness of these targeted agents is limited to relatively small subsets of TNBC patients[11,12,13] there is a critical need for more active therapeutic strategies. The activity of a series of phosphatases, including PP1, PP2A, and PPM1 (PP2C/PPM1A), as well as calcineurin, has been shown to have proapoptotic effects via dephosphorylation of BAD25,26

Methods

Results

Conclusion