MicroRNA-200 Family Modulation in Distinct Breast Cancer Phenotypes

被引:87
作者
Angeles Castilla, Maria [1 ,2 ]
Diaz-Martin, Juan [1 ,2 ]
Sarrio, David [3 ]
Romero-Perez, Laura [1 ,2 ]
Angeles Lopez-Garcia, Maria [1 ,2 ]
Vieites, Begona [1 ,2 ]
Biscuola, Michele [1 ,2 ]
Ramiro-Fuentes, Susana [1 ]
Isacke, Clare M. [3 ]
Palacios, Jose [1 ,2 ,4 ]
机构
[1] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Dept Pathol,Inst Biomed Sevilla, Seville, Spain
[2] RTICC, Madrid, Spain
[3] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England
[4] Hosp Univ Ramon Y Cajal, Dept Pathol, Madrid, Spain
来源
PLOS ONE | 2012年 / 7卷 / 10期
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-INITIATING CELLS; E-CADHERIN EXPRESSION; GENE-EXPRESSION; METAPLASTIC CARCINOMA; MIR-200; FAMILY; FEEDBACK LOOP; CLAUDIN-LOW; PROGRESSION; SUBTYPES;
D O I
10.1371/journal.pone.0047709
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas. We analyzed by qRT-PCR the expression of miR-200f members and various EMT-transcriptional inducers in a series of 70 breast cancers comprising an array of phenotypic subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative (TN), including a subset of metaplastic breast carcinomas (MBCs) with sarcomatous (homologous or heterologous) differentiation. No MBCs with squamous differentiation were included. The DNA methylation status of miR-200f loci in tumor samples were inspected using Sequenom MassArray (R) MALDI-TOF platform. We also used two non-tumorigenic breast basal cell lines that spontaneously undergo EMT to study the modulation of miR-200f expression during EMT in vitro. We demonstrate that miR-200f is strongly decreased in MBCs compared with other cancer types. TN and HER2+ breast cancers also exhibited lower miR-200f expression than ER+ tumors. Significantly, the decreased miR-200f expression found in MBCs is accompanied by an increase in the expression levels of EMT-transcriptional inducers, and hypermethylation of the miR-200c-141 locus. Similar to tumor samples, we demonstrated that downregulation of miR-200f and hypermethylation of the miR-200c-141 locus, together with upregulation of EMT-transcriptional inducers also occur in an in vitro cellular model of spontaneous EMT. Thus, the expression and methylation status of miR-200f could be used as hypothetical biomarkers to assess the occurrence of EMT in breast cancer.
引用
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页数:9
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