Claudia Palena1, Mario Roselli1, Mary T Litzinger1, Patrizia Ferroni1, Leopoldo Costarelli1, Antonella Spila1, Francesco Cavaliere1, Bruce Huang1, Romaine I Fernando1, Duane H Hamilton1, Caroline Jochems1, Kwong-Yok Tsang1, Qing Cheng1, H Kim Lyerly1, Jeffrey Schlom2, Fiorella Guadagni1. 1. Affiliations of authors: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (CP, MTL, BH, RIF, DHH, CJ, K-YT, JS); Department of Internal Medicine, Medical Oncology Unit, Tor Vergata University, Rome, Italy (MR); Interinstitutional Multidisciplinary Biobank, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy (PF, AS, FG); Department of Pathology (LC) and Department of Surgery (FC), San Giovanni Addolorata Hospital, Rome, Italy; Department of Surgery, Duke University School of Medicine, Durham, NC (QC, HKL). 2. Affiliations of authors: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (CP, MTL, BH, RIF, DHH, CJ, K-YT, JS); Department of Internal Medicine, Medical Oncology Unit, Tor Vergata University, Rome, Italy (MR); Interinstitutional Multidisciplinary Biobank, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele Pisana, Rome, Italy (PF, AS, FG); Department of Pathology (LC) and Department of Surgery (FC), San Giovanni Addolorata Hospital, Rome, Italy; Department of Surgery, Duke University School of Medicine, Durham, NC (QC, HKL). js141c@nih.gov.
Abstract
BACKGROUND: The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of human carcinoma cells. METHODS: Brachyury mRNA and protein expression was analyzed in human breast carcinomas and benign tissues. The role of brachyury in breast tumor prognosis and drug resistance and the ability of brachyury-specific T cells to lyse human breast carcinoma cells were also evaluated. Kaplan-Meier analyses were used to evaluate the association between brachyury expression and survival. All statistical tests were two-sided. RESULTS: The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancer patients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence (hazard ratio [HR] = 7.5; 95% confidence interval [CI] = 2.4 to 23.5; P = 5.14×10(-4)) and distant metastasis (HR = 15.2; 95% CI = 3.5 to 66.3; P = 3.01×10(-4)). We also demonstrated that brachyury-specific T cells can lyse human breast carcinoma cells. CONCLUSIONS: The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies. Published by Oxford University Press 2014.
BACKGROUND: The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of humancarcinoma cells. METHODS:Brachyury mRNA and protein expression was analyzed in humanbreast carcinomas and benign tissues. The role of brachyury in breast tumor prognosis and drug resistance and the ability of brachyury-specific T cells to lyse humanbreast carcinoma cells were also evaluated. Kaplan-Meier analyses were used to evaluate the association between brachyury expression and survival. All statistical tests were two-sided. RESULTS: The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancerpatients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence (hazard ratio [HR] = 7.5; 95% confidence interval [CI] = 2.4 to 23.5; P = 5.14×10(-4)) and distant metastasis (HR = 15.2; 95% CI = 3.5 to 66.3; P = 3.01×10(-4)). We also demonstrated that brachyury-specific T cells can lyse humanbreast carcinoma cells. CONCLUSIONS: The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of humanbreast cancer, either as a monotherapy or in combination therapies. Published by Oxford University Press 2014.
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