title: miR-296/Scribble axis is deregulated in human breast cancer and miR-296 restoration reduces tumour growth in vivo.
abstract: miR-296-5p is a central regulator of signalling pathways affecting development, stem cell differentiation and cancer. We hypothesized that miR-296-5p is involved in breast cancer onset and progression possibly through regulation of its target SCRIB (Scribble), a polarity protein recently implicated in the acquisition of cancer stem cell traits and in cell motility. We found that miR-296-5p levels were consistently reduced in human breast cancer tissues compared with non-neoplastic mammary parenchyma, and low expression of this miRNA predicted shorter disease-free survival independently of classic clinicopathological parameters. Further, reduced miR-296-5p levels were significantly correlated with an earlier spread of cancer in the overall series and with distant metastases in the subset. In contrast with its regulator, SCRIB was overexpressed and mislocalized in primary breast cancers or locoregional or distant metastatic lesions compared with normal parenchyma. Notably, SCRIB mislocalization was associated with overall survival, metastatic spread and organ tropism in patients with breast cancer. Finally, direct injection of a precursor miR-296-5p into tumours of a breast cancer xenograft model significantly decreased tumour growth. Our results show that the miR-296-5p/SCRIB axis plays a role in breast carcinogenesis and an miR-296-5p-based therapeutic approach hampers breast cancer tumour growth in vivo. Modulation of miR-296-5p may represent a new therapeutic option for patients with breast cancer.
authors: Federica
authors: F
authors: Savi
authors: Irene
authors: I
authors: Forno
authors: Alice
authors: A
authors: Faversani
authors: ‡Division of Medical Oncology, San Paolo Hospital, Milan, Italy.
authors: Andrea
authors: A
authors: Luciani
authors: ‡Division of Medical Oncology, San Paolo Hospital, Milan, Italy.
authors: Sarah
authors: S
authors: Caldiera
authors: §Center for Preclinical Surgical Research, University of Milan and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Stefano
authors: S
authors: Gatti
authors: Paolo
authors: P
authors: Foa
authors: †Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Milan, Italy.
authors: Dario
authors: D
authors: Ricca
authors: Gaetano
authors: G
authors: Bulfamante
authors: †Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Milan, Italy.
authors: Valentina
authors: V
authors: Vaira
authors: Silvano
authors: S
authors: Bosari
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C549871:MIRN296 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins