Sylvie Rodrigues-Ferreira1,2,3,4, Anne Nehlig1,2,3, Clarisse Monchecourt1,2,3, Sarah Nasr5, Laetitia Fuhrmann6, Magali Lacroix-Triki5, Ingrid Garberis1,2,3, Véronique Scott1,2,3, Suzette Delaloge5, Barbara Pistilli5, Philippe Vielh7, Thierry Dubois8, Anne Vincent-Salomon6, Fabrice André1,2,3, Clara Nahmias9,10,11. 1. Department of Molecular Medicine, INSERM U981, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94800, Villejuif, France. 2. LabEx LERMIT, University Paris Saclay, 5 Rue J-B Clément, 92296, Châtenay-Malabry, France. 3. University Paris Sud, 63 rue Gabriel Peri, 94270, Le Kremlin-Bicetre, France. 4. Inovarion, 75013, Paris, France. 5. Department of Medical Oncology, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94800, Villejuif, France. 6. Pathology Department, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France. 7. Department of Medical Biology and Pathology, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94805, Villejuif, France. 8. Translational Research Department, Breast Cancer Biology Group, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005 Paris, France. 9. Department of Molecular Medicine, INSERM U981, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94800, Villejuif, France. clara.nahmias@inserm.fr. 10. LabEx LERMIT, University Paris Saclay, 5 Rue J-B Clément, 92296, Châtenay-Malabry, France. clara.nahmias@inserm.fr. 11. University Paris Sud, 63 rue Gabriel Peri, 94270, Le Kremlin-Bicetre, France. clara.nahmias@inserm.fr.
Abstract
PURPOSE: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis. METHODS: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies. RESULTS: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results. CONCLUSIONS: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.
PURPOSE: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis. METHODS: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancerpatients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies. RESULTS: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results. CONCLUSIONS: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.
Entities:
Keywords:
Biomarkers combination; Breast cancer; Diagnosis; MAPRE1; MTUS1; Prognosis