BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer
| Autor: | William M. Gallagher, David Matallanas, Emer Conroy, Amanda McCann, Judith A. Coppinger, Zivile Useckaite, Mark Ward, Tony O'Grady, Darran P. O'Connor, Rebecca Reilly, Eugene M. Dempsey, Anthony J. Chubb, Kate Connor, Alo McGoldrick, Sarah Shields, Elaine W. Kay, Yue Fan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
EGFR Proliferation Estrogen receptor Signalling 03 medical and health sciences Breast cancer Medicine Epidermal growth factor receptor PI3K/AKT/mTOR pathway Triple-negative breast cancer Cancer Cetuximab biology business.industry BAG3 Correction medicine.disease 030104 developmental biology Oncology Cancer cell Cancer research biology.protein business TNBC medicine.drug |
| Zdroj: | Oncotarget |
| Popis: | // Sarah Shields 1 , Emer Conroy 1 , Tony O’Grady 5 , Alo McGoldrick 1 , Kate Connor 4 , Mark P. Ward 4 , Zivile Useckaite 4 , Eugene Dempsey 6 , Rebecca Reilly 1 , Yue Fan 1 , Anthony Chubb 4 , David Gomez Matallanas 2, 3 , Elaine W. Kay 5 , Darran O’Connor 4 , Amanda McCann 1, 2 , William M. Gallagher 1 and Judith A. Coppinger 1, 4 1 UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland 2 UCD School of Medicine, University College Dublin, Dublin 4, Ireland 3 Systems Biology Ireland, University College, Dublin 4, Ireland 4 Royal College of Surgeons in Ireland, Dublin 2, Ireland 5 Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland 6 School 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|