Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:3144.

BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer

Sarah Sheilds, Emer Conroy, Tony O'Grady, Alo McGoldrick, Kate Connor, Mark P. Ward, Zivile Useckaite, Eugene Dempsey, Rebecca Reilly, Yue Fan, Anthony Chubb, David Gomez Matallanas, Elaine W. Kay, Darran O'Connor, Amanda McCann, William M. Gallagher and Judith A. Coppinger _

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Oncotarget. 2018; 9:15673-15690. https://doi.org/10.18632/oncotarget.24590

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Abstract

Sarah Shields1, Emer Conroy1, Tony O’Grady5, Alo McGoldrick1, Kate Connor4, Mark P. Ward4, Zivile Useckaite4, Eugene Dempsey6, Rebecca Reilly1, Yue Fan1, Anthony Chubb4, David Gomez Matallanas2,3, Elaine W. Kay5, Darran O’Connor4, Amanda McCann1,2, William M. Gallagher1 and Judith A. Coppinger1,4

1UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland

2UCD School of Medicine, University College Dublin, Dublin 4, Ireland

3Systems Biology Ireland, University College, Dublin 4, Ireland

4Royal College of Surgeons in Ireland, Dublin 2, Ireland

5Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland

6School of Biology and Environmental Science, University College Dublin, Dublin 4, Ireland

Correspondence to:

Judith A. Coppinger, email: judithcoppinger@rcsi.ie

Keywords: TNBC; BAG3; EGFR; signalling; proliferation

Received: May 25, 2017     Accepted: February 21, 2018     Epub: February 28, 2018     Published: March 20, 2018

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.


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