Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer.

Abstract

PURPOSE:

The epithelial-mesenchymal transition (EMT) is emerging as a critical factor for the progression and metastasis of carcinomas, as well as drug resistance. The T-box transcription factor Brachyury has been recently characterized as a driver of EMT in human carcinoma cells. The purpose of this study was to characterize Brachyury as a potential target for lung cancer therapy.

EXPERIMENTAL DESIGN:

The expression of Brachyury was evaluated by PCR and by immunohistochemistry in human lung tumors and adult normal tissues. Brachyury gene copy number and promoter methylation status were analyzed in tumor tissues with various levels of Brachyury expression. Lung carcinoma cells' susceptibility to T-cell lysis and EGF receptor (EGFR) kinase inhibition were also evaluated relative to the levels of Brachyury.

RESULTS:

Our results showed Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury-positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition.

CONCLUSION:

We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer.

• Authors: Mario Roselli, Romaine I Fernando, Fiorella Guadagni, Antonella Spila, Jhessica Alessandroni, Raffaele Palmirotta, Leopoldo Costarelli, Mary Litzinger, Duane Hamilton, Bruce Huang, Joanne Tucker, Kwong-Yok Tsang, Jeffrey Schlom, Claudia Palena
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 14 Pg. 3868-79 (Jul 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22611028 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fetal Proteins
• T-Box Domain Proteins
• EGFR protein, human
• ErbB Receptors
• Brachyury protein

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Disease Progression
• Epithelial-Mesenchymal Transition
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Fetal Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis
• T-Box Domain Proteins (genetics, metabolism)