Journal Article

Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer

Nuovo, Gerard, Sasso, Marianna, Taccioli, Cristian, Iorio, Marilena V., Di Leva, Gianpiero, Plantamura, Ilaria, Casalini, Patrizia, Triulzi, Tiziana, Piovan, Claudia, Croce, Carlo M., Tortoreto, Monica, Palmieri, Dario, Braccioli, Luca, Tagliabue, Elda

2012

Overview

An increasing body of evidence highlights an intriguing interaction between microRNAs and transcriptional factors involved in determining cell fate, including the well known “genome guardian” p53. Here we show that miR-205, oncosuppressive microRNA lost in breast cancer, is directly transactivated by oncosuppressor p53. Moreover, evaluating miR-205 expression in a panel of cell lines belonging to the highly aggressive triple negative breast cancer (TNBC) subtype, which still lacks an effective targeted therapy and characterized by an extremely undifferentiated and mesenchymal phenotype, we demonstrated that this microRNA is critically down-expressed compared to a normal-like cell line. Re-expression of miR-205 where absent strongly reduces cell proliferation, cell cycle progression and clonogenic potential in vitro, and inhibits tumor growth in vivo, and this tumor suppressor activity is at least partially exerted through targeting of E2F1, master regulator of cell cycle progression, and LAMC1, component of extracellular matrix involved in cell adhesion, proliferation and migration. ► miR-205 is downregulated in triple negative breast cancer. ► miR-205 directly targets LAMC1 and E2F1. ► miR-205 inhibits cellular proliferation in vitro and in vivo. ► miR-205 induces cellular senescence. ► p53 regulates miR-205 expression.

• Publisher: Elsevier B.V,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Base Sequence / Binding sites / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cell adhesion / Cell adhesion & migration / Cell cycle / Cell Cycle - genetics / Cell fate / Cell Line, Tumor / Cell migration / Cell Proliferation / Cellular Senescence - genetics / Cloning / Down-Regulation - genetics / E2F1 / E2F1 Transcription Factor - metabolism / Experiments / Extracellular matrix / Female / Gene Expression Regulation, Neoplastic / Genomes / Humans / Kinases / LAMC1 / Laminin - metabolism / Mesenchyme / Mice / Mice, SCID / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miR-205 / miRNA / Molecular Sequence Data / Mutagenesis / Mutation / p53 / p53 Protein / Penicillin / Phenotypes / Plasmids / Protein Binding / Regulation / Response Elements - genetics / Transcription / Transcription factors / Transcription, Genetic / Tumor suppressor genes / Tumor Suppressor Protein p53 - metabolism / Xenograft Model Antitumor Assays