title: Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer.
abstract: Deregulated expression of microRNAs has been associated with angiogenesis. Studying the miRNome of locally advanced breast tumors we unsuspectedly found a dramatically repression of miR-204, a small non-coding RNA with no previous involvement in tumor angiogenesis. Downregulation of miR-204 was confirmed in an independent cohort of patients and breast cancer cell lines. Gain-of-function analysis indicates that ectopic expression of miR-204 impairs cell proliferation, anchorage-independent growth, migration, invasion, and the formation of 3D capillary networks in vitro. Likewise, in vivo vascularization and angiogenesis were suppressed by miR-204 in a nu/nu mice model. Genome-wide profiling of MDA-MB-231 cells expressing miR-204 revealed changes in the expression of hundred cancer-related genes. Of these, we focused on the study of pro-angiogenic ANGPT1 and TGFβR2. Functional analysis using luciferase reporter and rescue assays confirmed that ANGPT1 and TGFβR2 are novel effectors downstream of miR-204. Accordingly, an inverse correlation between miR-204 and ANGPT1/TGFβR2 expression was found in breast tumors. Knockdown of TGFβR2, but not ANGPT1, impairs cell proliferation and migration whereas inhibition of both genes inhibits angiogenesis. Taken altogether, our findings reveal a novel role for miR-204/ANGPT1/TGFβR2 axis in tumor angiogenesis. We propose that therapeutic manipulation of miR-204 levels may represent a promising approach in breast cancer.
authors.affiliation: Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
authors.forename: Ali
authors.initials: A
authors.lastname: Flores-Pérez
authors.affiliation: Programa en Biomedicina Molecular y Red de Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Marchat
authors.affiliation: Instituto de Enfermedades de la Mama, FUCAM, Ciudad de México, México.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodríguez-Cuevas
authors.affiliation: Instituto de Enfermedades de la Mama, FUCAM, Ciudad de México, México.
authors.forename: Verónica
authors.initials: V
authors.lastname: Bautista-Piña
authors.affiliation: Laboratorio de Genómica, Instituto Nacional de Medicina Genómica, Ciudad de México, México.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Hidalgo-Miranda
authors.affiliation: Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Ciudad de México, México.
authors.forename: Elena Aréchaga
authors.initials: EA
authors.lastname: Ocampo
authors.affiliation: Laboratorio de Genética y Diagnóstico Molecular, Hospital Juárez, Ciudad de México, México.
authors.forename: Mónica Sierra
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Palma-Flores
authors.affiliation: Departamento de Genética Humana, Hospital General de Mexico "Dr Eduardo Liceaga", Ciudad de México, México.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fonseca-Sánchez
authors.affiliation: Laboratorio de Investigación en Cáncer Translacional y Terapia Celular, Centro Médico Siglo XXI, Ciudad de México, México.
authors.forename: Horacio
authors.initials: H
authors.lastname: Astudillo-de la Vega
authors.affiliation: Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, Ciudad de México, México.
authors.forename: Erika
authors.initials: E
authors.lastname: Ruíz-García
authors.affiliation: Laboratorio de Medicina Genómica, Hospital Regional 1 de Octubre ISSSTE, Ciudad de México, México.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: González-Barrios
authors.affiliation: Laboratorio de Genómica, Instituto Nacional de Cancerología, Ciudad de México, México; Universidad Nacional Autónoma de México UNAM, FES-Iztacala, UBIMED, Tlalnepantla, Estado de México, México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Plasencia
authors.affiliation: Laboratorio de Investigación Experimental y Animal. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.
authors.forename: María L
authors.initials: ML
authors.lastname: Streber
authors.affiliation: Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
authors.forename: César
authors.initials: C
authors.lastname: López-Camarillo
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II