Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer
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Tommaso De Marchi1, Anne M. Timmermans1, Marcel Smid1, Maxime P. Look1, Christoph Stingl2, Mark Opdam3, Sabine C. Linn3, Fred C. G. J. Sweep4, Paul N. Span5, Mike Kliffen6, Carolien H. M. van Deurzen7, Theo M. Luider2, John A. Foekens1, John W. Martens1,8, Arzu Umar1
1Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
2Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands
3Division of Medical Oncology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
4Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
5Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
6Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands
7Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
8Cancer Genomics Center Netherlands, Amsterdam, The Netherlands
Tommaso De Marchi, e-mail: [email protected]
Keywords: tamoxifen resistance, annexin-A1, caldesmon, clinical proteomics, metastatic breast cancer
Received: July 30, 2015 Accepted: November 16, 2015 Published: December 09, 2015
Tamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent breast cancer. ANXA1 and CALD1, which were not included in the classifier, were however the most differentially expressed proteins. We first evaluated the clinical relevance of these markers in our MS cohort, followed by immunohistochemical (IHC) staining on an independent set of tumors incorporated in a tissue microarray (TMA) and regression analysis in relation to time to progression (TTP), clinical benefit and objective response. In order to assess which mechanisms ANXA1 and CALD1 might been involved in, we performed Ingenuity pathway analysis (IPA) on ANXA1 and CALD1 correlated proteins in our MS cohort. ANXA1 (Hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.22–2.75; P = 0.003) and CALD1 (HR = 1.57; 95% CI: 1.04–2.36; P = 0.039) based patient stratification showed significant association to TTP, while IHC staining on TMA showed that both ANXA1 (HR = 1.82; 95% CI: 1.12–3.00; P = 0.016) and CALD1 (HR = 2.29; 95% CI: 1.40–3.75; P = 0.001) expression was associated with shorter TTP independently of traditional predictive factors. Pearson correlation analysis showed that the majority of proteins correlated to ANXA1 also correlated with CALD1. IPA indicated that ANXA1 and CALD1 were associated with ER-downregulation and NFκB signaling. We hereby report that ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome and are associated to fast tumor progression.
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