title: The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer.
abstract: Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Debashish
authors.initials: D
authors.lastname: Sahay
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Leblanc
authors.affiliation: Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany.
authors.forename: Thomas G P
authors.initials: TG
authors.lastname: Grunewald
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Srikant
authors.initials: S
authors.lastname: Ambatipudi
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Johnny
authors.initials: J
authors.lastname: Ribeiro
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peyruchaud
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D008246:Lysophospholipids; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C032881:lysophosphatidic acid
keywords: ZEB1; breast cancer; lysophosphatidic acid; metastasis; miR-21