Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings
Abstract Background Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate...
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2018-11-01
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Series: | Breast Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13058-018-1064-1 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Astrid O. Leech Sri HariKrishna Vellanki Emily J. Rutherford Aoife Keogh Hanne Jahns Lance Hudson Norma O’Donovan Siham Sabri Bassam Abdulkarim Katherine M. Sheehan Elaine W. Kay Leonie S. Young Arnold D. K. Hill Yvonne E. Smith Ann M. Hopkins |
spellingShingle |
Astrid O. Leech Sri HariKrishna Vellanki Emily J. Rutherford Aoife Keogh Hanne Jahns Lance Hudson Norma O’Donovan Siham Sabri Bassam Abdulkarim Katherine M. Sheehan Elaine W. Kay Leonie S. Young Arnold D. K. Hill Yvonne E. Smith Ann M. Hopkins Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings Breast Cancer Research JAM-A Tight junction HER2 Breast cancer Drug resistance HER2-targeted therapies |
author_facet |
Astrid O. Leech Sri HariKrishna Vellanki Emily J. Rutherford Aoife Keogh Hanne Jahns Lance Hudson Norma O’Donovan Siham Sabri Bassam Abdulkarim Katherine M. Sheehan Elaine W. Kay Leonie S. Young Arnold D. K. Hill Yvonne E. Smith Ann M. Hopkins |
author_sort |
Astrid O. Leech |
title |
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings |
title_short |
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings |
title_full |
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings |
title_fullStr |
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings |
title_full_unstemmed |
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings |
title_sort |
cleavage of the extracellular domain of junctional adhesion molecule-a is associated with resistance to anti-her2 therapies in breast cancer settings |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2018-11-01 |
description |
Abstract Background Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. Methods Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. Results Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. Conclusions Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies. |
topic |
JAM-A Tight junction HER2 Breast cancer Drug resistance HER2-targeted therapies |
url |
http://link.springer.com/article/10.1186/s13058-018-1064-1 |
work_keys_str_mv |
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doaj-72a1a9c60a1942e4bc9a56db7d21098a2021-03-02T08:57:40ZengBMCBreast Cancer Research1465-542X2018-11-0120111810.1186/s13058-018-1064-1Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settingsAstrid O. Leech0Sri HariKrishna Vellanki1Emily J. Rutherford2Aoife Keogh3Hanne Jahns4Lance Hudson5Norma O’Donovan6Siham Sabri7Bassam Abdulkarim8Katherine M. Sheehan9Elaine W. Kay10Leonie S. Young11Arnold D. K. Hill12Yvonne E. Smith13Ann M. Hopkins14Department of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalPathobiology Section, School of Veterinary Medicine, University College DublinDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalNational Institute for Cellular Biotechnology, Dublin City UniversityDepartment of Pathology, McGill University, Faculty of Medicine, Department of PathologyDepartment of Oncology, McGill University, Faculty of Medicine, Department of OncologyDepartment of Pathology, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Pathology, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalDepartment of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont HospitalAbstract Background Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. Methods Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. Results Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. Conclusions Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.http://link.springer.com/article/10.1186/s13058-018-1064-1JAM-ATight junctionHER2Breast cancerDrug resistanceHER2-targeted therapies |