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HER2/HER3 heterodimers and p21 expression are capable of predicting adjuvant trastuzumab response in HER2+ breast cancer

Green, Andrew R.; Barros, Fabr�cio F.T.; Abdel-Fatah, Tarek M.A.; Moseley, Paul; Nolan, Christopher C.; Durham, Alice C.; Rakha, Emad A.; Chan, Stephen; Ellis, Ian O.

HER2/HER3 heterodimers and p21 expression are capable of predicting adjuvant trastuzumab response in HER2+ breast cancer Thumbnail


Authors

Fabr�cio F.T. Barros

Tarek M.A. Abdel-Fatah

Paul Moseley

Christopher C. Nolan

Alice C. Durham

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Stephen Chan



Abstract

Human epidermal growth factor receptor 2 (HER2) plays an important role in breast cancer progression and provides predictive information for response to targeted therapy including trastuzumab although this is limited. Downstream pathways, such as PI3K/Akt, are associated with HER2/HER3 heterodimerization promoting survival and proliferation amongst cancer cells. Thus, patient outcome and trastuzumab therapy effectiveness might be further characterised by HER2/HER3 dimerisation and its signalling pathways. HER2/HER3 dimerisation status was assessed, using chromogenic in situ Proximity Ligation Assay, in two breast cancer series: early stage primary breast cancer, including 224 HER2+ patients that were not submitted to trastuzumab, and HER2+ breast cancer where patients were treated with adjuvant trastuzumab (n = 143). Levels of biomarkers including PI3K, pAKT, ER, PgR, HER3, BCL2, p53, PTEN and p21 were measured using immunohistochemistry. Levels of HER2/HER3 heterodimers were compared with biomarker expression and patient outcome. An association between high levels of HER2/HER3 dimerisation and absence of hormone receptors, ER and PgR, was observed. We further show for the first time the presence of HER2/HER3 heterodimers and the loss of p21 expression in HER2+ breast cancer predicts a significantly poorer outcome when submitted to adjuvant trastuzumab. Breast cancer patients that reveal high levels of HER2/HER3 dimerisation and loss of p21 are associated with poor survival prognosis in patients with HER2+ breast cancer treated with adjuvant trastuzumab. Further quantification analysis of HER dimer/ligand complexes and downstream signalling pathways will begin to unravel the complex associations with patient outcome and its relationship with sensitivity to targeted treatment.

Citation

Green, A. R., Barros, F. F., Abdel-Fatah, T. M., Moseley, P., Nolan, C. C., Durham, A. C., …Ellis, I. O. (2014). HER2/HER3 heterodimers and p21 expression are capable of predicting adjuvant trastuzumab response in HER2+ breast cancer. Breast Cancer Research and Treatment, 145(1), 33-44. https://doi.org/10.1007/s10549-014-2925-7

Journal Article Type Article
Acceptance Date Mar 17, 2014
Online Publication Date Apr 6, 2014
Publication Date 2014-05
Deposit Date Oct 17, 2018
Publicly Available Date Oct 17, 2018
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 145
Issue 1
Pages 33-44
DOI https://doi.org/10.1007/s10549-014-2925-7
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/1172490
Publisher URL https://link.springer.com/article/10.1007%2Fs10549-014-2925-7
Contract Date Oct 17, 2018

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