TRIM24 links glucose metabolism with transformation of human mammary epithelial cells

• Published in: Oncogene 2015-05, Vol.34 (22), p.2836-2845
• Main Authors: Pathiraja, T N, Thakkar, K N, Jiang, S, Stratton, S, Liu, Z, Gagea, M, Shi, X, Shah, P K, Phan, L, Lee, M-H, Andersen, J, Stampfer, M, Barton, M C
• Format: Article
• Language: English
• Subjects: 13; 38; 45; 45/43; 631/337; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carrier Proteins - physiology; Cell Biology; Cell culture; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells; Cells, Cultured; Development and progression; Ectopic expression; Energy Metabolism - genetics; Epithelial cells; Female; Flowers & plants; Genetic aspects; Genetic transformation; Glucose; Glucose - metabolism; Glycolysis; Health aspects; HEK293 Cells; Homeobox; Human Genetics; Humans; Innovations; Internal Medicine; Mammary gland; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; MCF-7 Cells; Medicine; Medicine & Public Health; Metabolism; Mice; Mice, Nude; Molecular targeted therapy; Oncology; original-article; p53 Protein; Properties; Therapeutic applications; Transcription factors; Tricarboxylic acid cycle; Tumorigenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.220

Tripartite motif 24 protein (TRIM24) is a plant homeodomain/bromodomain histone reader, recently associated with poor overall survival of breast-cancer patients. At a molecular level, TRIM24 is a negative regulator of p53 levels and a co-activator of estrogen receptor. However, the role of TRIM24 in breast tumorigenesis remains largely unknown. We used an isogenic human mammary epithelial cell (HMEC) culture model, derived from reduction mammoplasty tissue, and found that ectopic expression of TRIM24 in immortalized HMECs (TRIM24 iHMECs) greatly increased cellular proliferation and induced malignant transformation. Subcutaneous injection of TRIM24 iHMECs in nude mice led to growth of intermediate to high-grade tumors in 60–70% of mice. Molecular analysis of TRIM24 iHMECs revealed a glycolytic and tricarboxylic acid cycle gene signature, alongside increased glucose uptake and activated aerobic glycolysis. Collectively, these results identify a role for TRIM24 in breast tumorigenesis through reprogramming of glucose metabolism in HMECs, further supporting TRIM24 as a viable therapeutic target in breast cancer.