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.

Details

Title
Expression of the BAD pathway is a marker of triple-negative status and poor outcome
Author
Boac, Bernadette M 1 ; Abbasi, Forough 2 ; Ismail-Khan, Roohi 3 ; Xiong, Yin 1 ; Siddique, Atif 4 ; Park, Hannah 1 ; Han, Mingda 1 ; Saeed-Vafa, Daryoush 4 ; Soliman, Hatem 3 ; Henry, Brendon 4 ; Pena, M Juliana 4 ; McClung, E Clair 5 ; Robertson, Sharon E 6 ; Todd, Sarah L 7 ; Lopez, Alex 4 ; Sun, Weihong 7 ; Apuri, Susmitha 7 ; Lancaster, Johnathan M 8 ; Berglund, Anders E 9   VIAFID ORCID Logo  ; Magliocco, Anthony M 10 ; Marchion, Douglas C 1 

1  Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
2  Cedars-Sinai Medical Center, Los Angeles, CA, USA 
3  Department of Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Women’s Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
4  Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
5  University of Arizona Cancer Center, Obstetrics and Gynecology, Tucson, AZ, USA 
6  Indiana University Health, Indianapolis, IN, USA 
7  Department of Women’s Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
8  Myriad Genetics, Salt Lake City, UT, USA 
9  Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
10  Protean Diagnostics, Tampa, FL, USA 
Pages
1-14
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-53695-0
ProQuest document ID
2317948394
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.