Spears, M., Taylor, K.J., Munro, A.F., Cunningham, C.A., Mallon, E.A., Twelves, C.J., Cameron, D.A., Thomas, J. and Bartlett, J.M.S. (2012) In situ detection of HER2:HER2 and HER2:HER3 protein–protein interactions demonstrates prognostic significance in early breast cancer. Breast Cancer Research and Treatment, 132(2), pp. 463-470. (doi: 10.1007/s10549-011-1606-z)
Full text not currently available from Enlighten.
Abstract
HER2 overexpression/amplification is linked with poor prognosis in early breast cancer. Co-expression of HER2 and HER3 is associated with endocrine and chemotherapy resistance, driven not simply by expression but by signalling via HER2:HER3 or HER2:HER2 dimers. Proximity ligation assays (PLAs) detect protein–protein complexes at a single-molecule level and allow study of signalling pathways in situ. A cohort of 100 tumours was analyzed by PLA, IHC and FISH. HER complexes were analyzed by PLA in a further 321 tumours from the BR9601 trial comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with epirubicin followed by CMF (epi-CMF). The relationships between HER dimer expression and RFS and OS were investigated, and multivariate regression analysis identified factors influencing patient prognosis. PLA successfully and reproducibly detected HER2:HER2 and HER2:HER3 protein complexes in vivo. A significant association (P < 0.00001) was identified between HER2 homodimerization and HER2 gene amplification. Following a minimum p value approach high levels of HER2:HER2 dimers were significantly associated with reduced relapse-free (RFS; hazard ratio = 1.72, 95% confidence interval 1.15–2.56, P = 0.008) and overall survival (OS HR = 1.69 95% CI = 1.09–2.62, P = 0.019). Similarly, high levels of HER2:HER3 dimers were associated with reduced RFS (HR = 2.18, 95% CI = 1.46–3.26, P = 0.00016) and OS (HR = 2.21, 95% CI = 1.41–3.47, P = 0.001). This study demonstrates that in situ detection of HER2 and HER2:3 protein:protein complexes can be performed robustly and reproducibly in clinical specimens, provides novel prognostic information and opens a significant novel opportunity to probe the clinical impact of cellular signalling processes.
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Mallon, Dr Elizabeth |
Authors: | Spears, M., Taylor, K.J., Munro, A.F., Cunningham, C.A., Mallon, E.A., Twelves, C.J., Cameron, D.A., Thomas, J., and Bartlett, J.M.S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
Journal Name: | Breast Cancer Research and Treatment |
ISSN: | 0167-6806 |
Published Online: | 03 June 2011 |
University Staff: Request a correction | Enlighten Editors: Update this record