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

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 b...

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Bibliographic Details
Published in:Molecular oncology 2012-08, Vol.6 (4), p.458-472
Main Authors: Piovan, Claudia, Palmieri, Dario, Di Leva, Gianpiero, Braccioli, Luca, Casalini, Patrizia, Nuovo, Gerard, Tortoreto, Monica, Sasso, Marianna, Plantamura, Ilaria, Triulzi, Tiziana, Taccioli, Cristian, Tagliabue, Elda, Iorio, Marilena V., Croce, Carlo M.
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:1574-7891
1878-0261
DOI:10.1016/j.molonc.2012.03.003