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Sci Rep. 2016 Oct 5;6:34504. doi: 10.1038/srep34504.

Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer.

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Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
Programa en Biomedicina Molecular y Red de Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México.
Instituto de Enfermedades de la Mama, FUCAM, Ciudad de México, México.
Laboratorio de Genómica, Instituto Nacional de Medicina Genómica, Ciudad de México, México.
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Ciudad de México, México.
Laboratorio de Genética y Diagnóstico Molecular, Hospital Juárez, Ciudad de México, México.
Departamento de Genética Humana, Hospital General de Mexico "Dr Eduardo Liceaga", Ciudad de México, México.
Laboratorio de Investigación en Cáncer Translacional y Terapia Celular, Centro Médico Siglo XXI, Ciudad de México, México.
Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, Ciudad de México, México.
Laboratorio de Medicina Genómica, Hospital Regional 1 de Octubre ISSSTE, Ciudad de México, México.
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.
Laboratorio de Investigación Experimental y Animal. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.


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.

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