Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition

• Published in: The Journal of pathology 2011-05, Vol.224 (1), p.78-89
• Main Authors: Yuen, Hiu-Fung, Chan, Yuen-Kwong, Grills, Claire, McCrudden, Cian M, Gunasekharan, Vignesh, Shi, Zhanzhong, Wong, Ashley San-Yu, Lappin, Terence R, Chan, Kwok-Wah, Fennell, Dean A, Khoo, Ui-Soon, Johnston, Patrick G, El-Tanani, Mohamed
• Format: Article
• Language: English
• Subjects: Adenovirus E1A Proteins - metabolism; Adenovirus E1A Proteins - physiology; Biological and medical sciences; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Nucleus - metabolism; Cell survival; Data processing; Disease Progression; Enhancers; Epidemiologic Methods; Epithelial cells; epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - physiology; Female; Gene expression; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Infectious diseases; Invasiveness; Investigative techniques, diagnostic techniques (general aspects); Lung; Mammary gland diseases; Medical sciences; Metastases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; Ovarian cancer; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pea3; Polyomavirus; Prognosis; Promoter Regions, Genetic; Promoters; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; Reverse Transcriptase Polymerase Chain Reaction - methods; Snail; Snail Family Transcription Factors; snail protein; Transcription Factors - genetics; Transcription Factors - physiology; Tumor cell lines; Tumor Cells, Cultured; Tumors; Viral diseases
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2859

Polyomavirus enhancer activator 3 protein (Pea3), also known as ETV4, is a member of the Ets‐transcription factor family, which promotes metastatic progression in various types of solid cancer. Pea3‐driven epithelial‐mesenchymal transition (EMT) has been described in lung and ovarian cancers. The mechanisms of Pea3‐induced EMT, however, are largely unknown. Here we show that Pea3 overexpression promotes EMT in human breast epithelial cells through transactivation of Snail (SNAI1), an activator of EMT. Pea3 binds to the human Snail promoter through the two proximal Pea3 binding sites and enhances Snail expression. In addition, knockdown of Pea3 in invasive breast cancer cells results in down‐regulation of Snail, partial reversal of EMT, and reduced invasiveness in vitro. Moreover, knockdown of Snail partially rescues the phenotype induced by Pea3 overexpression, suggesting that Snail is one of the mediators bridging Pea3 and EMT, and thereby metastatic progression of the cancer cells. In four breast cancer patient cohorts whose microarray and survival data were obtained from the Gene Expression Omnibus database, Pea3 and Snail expression are significantly correlated with each other and with overall survival of breast cancer patients. We further demonstrate that nuclear localization of Pea3 is associated with Snail expression in breast cancer cell lines and is an independent predictor of overall survival in a Chinese breast cancer patient cohort. In conclusion, our results suggest that Pea3 may be an important prognostic marker and a therapeutic target for metastatic progression of human breast cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.