miR-296/Scribble axis is deregulated in human breast cancer and miR-296 restoration reduces tumour growth in vivo

被引:42
作者
Savi, Federica [1 ,2 ]
Forno, Irene [1 ,2 ]
Faversani, Alice [1 ,2 ]
Luciani, Andrea [3 ]
Caldiera, Sarah [3 ]
Gatti, Stefano [4 ,5 ]
Foa, Paolo [3 ,6 ]
Ricca, Dario [2 ]
Bulfamante, Gaetano [6 ,7 ]
Vaira, Valentina [2 ]
Bosari, Silvano [1 ,2 ]
机构
[1] Univ Milan, Dept Pathophysiol & Organ Transplantat, Milan, Italy
[2] Policlin Milan, Osped Maggiore, Fdn IRCCS Ca Granda, Div Pathol, Milan, Italy
[3] San Paolo Hosp, Div Med Oncol, Milan, Italy
[4] Univ Milan, Ctr Preclin Surg Res, Milan, Italy
[5] Policlin Milan, Osped Maggiore, Fdn IRCCS Ca Granda, Milan, Italy
[6] Univ Milan, Dept Hlth Sci, Milan, Italy
[7] San Paolo Hosp, Div Pathol, Milan, Italy
关键词
breast carcinoma; microRNA; neoplasm metastasis and recurrence; prognosis; Scribble; CELL POLARITY; DISCS-LARGE; EXPRESSION; SCRIBBLE; PROTEIN; MIRNAS; OVEREXPRESSION; PROLIFERATION; METASTASIS; MICRORNAS;
D O I
10.1042/CS20130580
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:233 / 242
页数:10
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