Andrea Angius1, Giovanna Pira2, Paolo Cossu-Rocca3,4, Giovanni Sotgiu3, Laura Saderi3, Maria Rosaria Muroni3, Patrizia Virdis3, Daniela Piras5, Rallo Vincenzo1, Ciriaco Carru2, Donatella Coradduzza2, Maria Gabriela Uras3, Pierina Cottu3, Alessandro Fancellu3, Sandra Orrù6, Paolo Uva7, Maria Rosaria De Miglio8. 1. Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria Di Cagliari, 09042, Monserrato, CA, Italy. 2. Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy. 3. Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. 4. Department of Diagnostic Services, "Giovanni Paolo II" Hospital, ASSL Olbia-ATS Sardegna, 07026, Olbia, Italy. 5. Struttura Complessa Epidemiologia e Registro Tumori Nord Sardegna, ATS Sardegna, 07100, Sassari, Italy. 6. Department of Pathology, "A. Businco" Oncologic Hospital, ARNAS Brotzu, 09121, Cagliari, Italy. 7. IRCCS G. Gaslini, 16147, Genoa, Italy. 8. Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy. demiglio@uniss.it.
Abstract
PURPOSE: Triple negative breast cancer (TNBC) is an aggressive clinical tumor, accounting for about 25% of breast cancer (BC) related deaths. Chemotherapy is the only therapeutic option to treat TNBC, hence a detailed understanding of the biology and its categorization is required. To investigate the clinical relevance of BCL11A in TNBC subtype, we focused on gene and protein expression and its mutational status in a large cohort of this molecular subtype. METHODS: Gene expression profiling of BCL11A and its isoforms (BCL11A-XL, BCL11A-L and BCL11A-S) has been determined in Luminal A, Luminal B, HER2-enriched and TNBC subtypes. BCL11A protein expression has been analyzed by immunohistochemistry (IHC) and its mutational status by Sanger sequencing. RESULTS: In our study, BCL11A was significantly overexpressed in TNBC both at transcriptional and translational levels compared to other BC molecular subtypes. A total of 404 TNBCs were selected and examined showing a high prevalence of BCL11A-XL (37.3%) and BCL11A-L (31.4%) isoform expression in TNBC, associated with a 26% of BCL11A protein expression levels. BCL11A protein expression predicts scarce LIV (HR = 0.52; 95% CI, 0.29-0.92, P = 0.03) and AR downregulation (HR = 0.37; 95% CI, 0.16-0.88; P = 0.02), as well as a higher proliferative index in TNBC cells. BCL11A-L expression is associated with more aggressive TNBC histological types, such as medullary and metaplastic carcinoma. CONCLUSION: Our finding showed that BCL11A protein expression acts as an unfavorable prognostic factor in TNBC patients, especially in non luminal TNBCs subgroups. These results may yield a better treatment strategy by providing a new parameter for TNBC classification.
PURPOSE: Triple negative breast cancer (TNBC) is an aggressive clinical tumor, accounting for about 25% of breast cancer (BC) related deaths. Chemotherapy is the only therapeutic option to treat TNBC, hence a detailed understanding of the biology and its categorization is required. To investigate the clinical relevance of BCL11A in TNBC subtype, we focused on gene and protein expression and its mutational status in a large cohort of this molecular subtype. METHODS: Gene expression profiling of BCL11A and its isoforms (BCL11A-XL, BCL11A-L and BCL11A-S) has been determined in Luminal A, Luminal B, HER2-enriched and TNBC subtypes. BCL11A protein expression has been analyzed by immunohistochemistry (IHC) and its mutational status by Sanger sequencing. RESULTS: In our study, BCL11A was significantly overexpressed in TNBC both at transcriptional and translational levels compared to other BC molecular subtypes. A total of 404 TNBCs were selected and examined showing a high prevalence of BCL11A-XL (37.3%) and BCL11A-L (31.4%) isoform expression in TNBC, associated with a 26% of BCL11A protein expression levels. BCL11A protein expression predicts scarce LIV (HR = 0.52; 95% CI, 0.29-0.92, P = 0.03) and AR downregulation (HR = 0.37; 95% CI, 0.16-0.88; P = 0.02), as well as a higher proliferative index in TNBC cells. BCL11A-L expression is associated with more aggressive TNBC histological types, such as medullary and metaplastic carcinoma. CONCLUSION: Our finding showed that BCL11A protein expression acts as an unfavorable prognostic factor in TNBC patients, especially in non luminal TNBCs subgroups. These results may yield a better treatment strategy by providing a new parameter for TNBC classification.
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