HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status
Files in This Item:
|HER2-HER3 dimer quantification by FLIM-FRET predicts breast.pdf||8.69 MB||Adobe PDF||Download|
|Title:||HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status||Authors:||Weitsman, Gregory
Barber, Paul R.
Nguyen, Lan K.
Kholodenko, Boris N.
|Permanent link:||http://hdl.handle.net/10197/9758||Date:||7-Jul-2016||Online since:||2019-04-01T10:57:44Z||Abstract:||Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker. FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61–9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding. Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.||Funding Details:||European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
|Type of material:||Journal Article||Publisher:||Impact Journals||Journal:||Oncotarget||Volume:||7||Issue:||32||Start page:||51012||End page:||51026||Copyright (published version):||2016 the Authors||Keywords:||Breast cancer; HER2; HER3; FLIM-FRET; Prognosis||DOI:||10.18632/oncotarget.9963||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||SBI Research Collection|
Show full item record
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. For other possible restrictions on use please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.