title: Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition.
abstract: 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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University of Belfast, UK.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.forename: Yuen-Kwong
authors.initials: YK
authors.lastname: Chan
authors.forename: Claire
authors.initials: C
authors.lastname: Grills
authors.forename: Cian M
authors.initials: CM
authors.lastname: McCrudden
authors.forename: Vignesh
authors.initials: V
authors.lastname: Gunasekharan
authors.forename: Zhanzhong
authors.initials: Z
authors.lastname: Shi
authors.forename: Ashley San-Yu
authors.initials: AS
authors.lastname: Wong
authors.forename: Terence R
authors.initials: TR
authors.lastname: Lappin
authors.forename: Kwok-Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: Ui-Soon
authors.initials: US
authors.lastname: Khoo
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D004812:Epidemiologic Methods; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D017500:Adenovirus E1A Proteins; D014408:Biomarkers, Tumor; C079853:ETV4 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors