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

• DOI: 10.1038/srep34504
• Publication Date: 2016-10-05T09:58:08Z
• Authors: Ali Flores-Pérez; Laurence A. Marchat; Sergio Rodríguez-...; Verónica Bautista...; Alfredo Hidalgo-M...; Elena Aréchaga Oc...; Mónica Sierra Mar...; Carlos Palma-Flores; Miguel A. Fonseca...; Horacio Astudillo...; Erika Ruíz-García; Juan Antonio Gonz...; Carlos Pérez-Plas...; María L. Streber; César López-Camar...
• Keywords: 0303 health sciences; Neovascularization, Pathologic; Receptor, Transforming Growth Factor-beta Type II; Breast Neoplasms; Protein Serine-Threonine Kinases; Article; Neoplasm Proteins; 3. Good health; MicroRNAs; 03 medical and health sciences; Angiopoietin-1; MCF-7 Cells; Humans; Female; RNA, Neoplasm; Receptors, Transforming Growth Factor beta

AbstractDeregulated 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.