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Oncotarget. 2018 Sep 18;9(73):33762-33777. doi: 10.18632/oncotarget.26031. eCollection 2018 Sep 18.

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer.

Author information

1
Institut Paoli-Calmettes, Department of Medical Oncology, Marseille, France.
2
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille Proteomics, Marseille, France.
3
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology Team, Marseille, France.
4
IRCM, INSERM, Institut Régional du Cancer, Department of Medical Oncology, Montpellier, France.
5
Institut Paoli-Calmettes, Department of Anatomo-pathology, Marseille, France.
6
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Team, Marseille, France.

Abstract

Introduction:

treatments targeting the Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) have improved the natural history of HER2-positive breast cancer. However, except HER2 protein expression and gene amplification, there is no predictive biomarker to guide the HER2-targeted therapies. We developed Parallel reaction monitoring (PRM) a powerful approach, to quantify and evaluate key proteins involved in the HER2 pathway and/or anti-HER2 treatment sensitivity.

Results:

in BCLs, PRM measurements correlated with western blot immunocytochemistry and transcriptomic data. At baseline, higher expression of HER2, EGFR, PTEN and HER3 but lower expression of phospho-HER2 correlated with trastuzumab sensitivity. Under trastuzumab, PRM demonstrated a decrease in HER2 and an increase in phospho-HER2, which correlated with drug sensitivity. The opposite was observed under lapatinib. HER2 quantification was also correlated with immunohistochemistry in PDXs and clinical breast cancer samples.

Discussion:

in conclusion, PRM-based assay, developed to quantify proteins of the HER2 pathway in breast cancer samples revealed a large magnitude of expression, which may have relevance in terms of treatment sensitivity.

Materials and Methods:

we first evaluated PRM in term of sensitivity, linearity and reproducibility. PRM was then applied to breast cancer cell lines (BCLs) including BCLs exposed to anti-HER2 agents, patient-derived xenografts (PDXs) and frozen breast cancer samples.

KEYWORDS:

HER2-positive; breast cancer; mass spectrometry; parallel reaction monitoring; proteomics

Conflict of interest statement

CONFLICTS OF INTEREST Mathilde Guerin received research grant from Roche. Renaud Sabatier has been consultant for and received non-financial support from Roche. The other authors have no conflict of interest to declare.

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