title: Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition.
abstract: The epithelial-to-mesenchymal transition (EMT) process allows carcinoma cells to dissociate from the primary tumor thereby facilitating tumor cell invasion and metastasis. Ras-dependent hyperactive signaling is commonly associated with tumorigenesis, invasion, EMT, and metastasis. However, the downstream effectors by which Ras regulates EMT remain ill defined. In this study, we show that the H-Ras pathway leads to mesenchymal-like phenotypic changes in human breast epithelial cells by controlling the ZEB1/microRNA-200c axis. Moreover, H-Ras suppresses the expression of the discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine kinase, via ZEB1, thus identifying ZEB1 as a novel transcriptional repressor of DDR1. Mutation studies on the putative promoter of the DDR1 gene revealed that bipartite Z- and E-box elements play a key role in transcriptional repression of DDR1 in Hs578T and MDA-MB-231 breast carcinoma cell lines by ZEB1. Furthermore, we found an inverse correlation between ZEB1 and DDR1 expression in various cancer cell lines and in human breast carcinoma tissues. Consistently, overexpression of DDR1 reduced the invasive phenotype of mesenchymal-like triple-negative breast cancer cells in 3D cultures and in vivo. Thus, ZEB1's role in maintenance of EMT in breast carcinoma cells is mediated in part by its ability to suppress DDR1 expression and consequently contribute to the activation of the invasive phenotype. Taken together, our results unveil a novel H-Ras/ZEB1/DDR1 network that contributes to breast cancer progression in triple-negative breast cancers.
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Koh
authors.forename: Yunjung
authors.initials: Y
authors.lastname: Woo
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Valiathan
authors.forename: Hae Yoen
authors.initials: HY
authors.lastname: Jung
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Yong Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Hyeong-Reh Choi
authors.initials: HR
authors.lastname: Kim
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: Aree
authors.initials: A
authors.lastname: Moon
mesh_terms: D001940:Breast / Q000473:pathology*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000502:physiology; D000070818:Discoidin Domain Receptors; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology; D009024:Morphogenesis; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D011975:Receptors, Mitogen / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011975:Receptors, Mitogen; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: H-Ras; ZEB1; breast cancer; discoidin domain receptor 1; invasion