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BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer
Date Issued
2018-03-20
Date Available
2021-01-26T08:56:03Z
Abstract
Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.
Sponsorship
Science Foundation Ireland
Other Sponsorship
Irish Cancer Society Collaborative Cancer Research Centre
National Children’s Research Centre
Royal College of Surgeons in Ireland
Type of Material
Journal Article
Publisher
Impact Journals
Journal
Oncotarget
Volume
9
Issue
21
Start Page
15673
End Page
15690
Copyright (Published Version)
2018 the Authors
Language
English
Status of Item
Peer reviewed
ISSN
1949-2553
This item is made available under a Creative Commons License
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