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HER2 and β-catenin protein location: importance in the prognosis of breast cancer patients and their correlation when breast cancer cells suffer stressful situations

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Abstract

In human breast cancer, β-catenin localization has been related with disease prognosis. Since HER2-positive patients are an important subgroup, and that in breast cancer cells a direct interaction of β-catenin/HER2 has been reported, in the present study we have explored whether β-catenin location is related with the disease survival. The study was performed in a tumor bank from patients (n = 140) that did not receive specific anti-HER2 therapy. The proteins were detected by immunohistochemistry in serial sections, 47 (33.5 %) patients were HER2-positive with a long follow-up. HER2-positive patients that displayed β-catenin at the plasma membrane (completely surrounding the tumour cells) showed a significant better disease-free survival and overall survival than the patients showing the protein on other locations. Then we explored the dynamics of the co-expression of β-catenin and HER2 in human MCF-7 and SKBR3 cells exposed to different stressful situations. In untreated conditions MCF-7 and SKBR3 cells showed very different β-catenin localization. In MCF-7 cells, cadmium administration caused a striking change in β-catenin localization driving it from plasma membrane to cytoplasmic and perinuclear areas and HER2 showed a similar localization patterns. The changes induced by cadmium were compared with heat shock, H2O2 and tamoxifen treatments. In conclusion, this study shows the dynamical associations of HER2 and β-catenin and their changes in subcellular localizations driven by stressful situations. In addition, we report for the first time the correlation between plasma membrane associated β-catenin in HER2-positive breast cancer and survival outcome, and the importance of the protein localization in breast cancer samples.

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Acknowledgments

This work was supported by the National Research Council of Argentina (CONICET) (PIP to DRC). This work is part of the Thesis (DAO) for the PROBIOL, UNCuyo, Mendoza, Argentina.

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    Authors and Affiliations

    1. Laboratory of Oncology, Institute of Experimental Medicine and Biology of Cuyo (IMBECU), Technology and Scientific Center (CCT)-National Research Council of Argentina (CONICET), Ruiz Leal s/n, Parque General San Martín, 5500, Mendoza, Argentina

      F. Darío Cuello-Carrión, Jorge E. Shortrede, Daiana Alvarez-Olmedo, Niubys Cayado-Gutiérrez, Gisela N. Castro, Felipe C. M. Zoppino, Martín Guerrero, Mariel A. Fanelli & Daniel R. Ciocca

    2. Medical School, National University of Cuyo, and Italian Hospital, Mendoza, Argentina

      Javier Orozco, Francisco E. Gago & Leonardo A. Ciocca

    3. Laboratory of Analytical Chemistry for Development and Research (QUIANID), Faculty of Exact and Natural Sciences, National University of Cuyo, Mendoza, Argentina

      Estefania Martinis & Rodolfo Wuilloud

    4. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina

      Nidia N. Gómez

    5. IMIBIO-CONICET, Universidad Nacional de San Luis, San Luis, Argentina

      Verónica Biaggio

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    1. F. Darío Cuello-Carrión
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    Corresponding author

    Correspondence to Daniel R. Ciocca.

    Additional information

    F. Darío Cuello-Carrión, Jorge E. Shortrede, Mariel A. Fanelli and Daniel R. Ciocca have contributed equally to this work.

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    Supplementary figure (TIFF 56150 kb)

    Lipid peroxidation by Thiobarbituric acid-reactive substances (TBARS) in MCF-7 and SKBR3 cells. a Comparative graph of both cell lines after 0, 5, 100 µM Cd administration. b TBARS in MCF-7 cells following 18 µM tamoxifen and after tamoxifen + 5, or 100 µM Cd. TBARS in MCF-7 cells (c) after hyperthermia, hyperthermia + tamoxifen, and hyperthermia + H2O2. TBARS in SKBR3 cells (d) after hyperthermia, and hyperthermia + H2O2. The results represent mean ± SD at least three independent experiments, α = 0.05, *** P < 0.001

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    Cuello-Carrión, F.D., Shortrede, J.E., Alvarez-Olmedo, D. et al. HER2 and β-catenin protein location: importance in the prognosis of breast cancer patients and their correlation when breast cancer cells suffer stressful situations. Clin Exp Metastasis 32, 151–168 (2015). https://doi.org/10.1007/s10585-015-9694-5

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