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MiR-1246 association with distant metastasis and poor prognosis in breast cancer patients

ABSTRACT: Circulating microRNAs have recently emerged as a new class of promising non-invasive cancer biomarkers. The purpose of this study was the identification by a high-throughput approach (miRNA microarray) of circulating miRNAs associated with breast cancer-derived distant metastasis. To achieve this goal, we resorted to archival plasma samples collected from patients in the control arm of a randomized clinical trial on stage I breast cancer. We compared plasma miRNA levels in patients that developed distant metastasis after a radical or conservative surgery and in those long-term disease-free. Microarray results were technically and independently validated by Real Time PCR. Subsequent in vitro, in vivo and in silico analyses were performed to investigate the miRNA biological/clinical significance in relation with breast cancer progression. We demonstrated that high circulating miR-1246 levels were associated to distant metastasis and that high tissue expression of this miRNA was correlated with unfavorable outcome in ER+HER2- breast cancer patients. In addition, miR-1246 expression was also found to be related with stem-like features.

ORGANISM(S): Homo sapiens

PROVIDER: GSE68373 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA282533

REPOSITORIES: GEO

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Project description:Introduction: microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin. To our knowledge, circulating exosome microRNAs have not been well evaluated as biomarkers for breast cancer diagnosis or monitoring. Methods: Exosomes were collected from the conditioned media of human breast cancer cell lines, mouse plasma of patient-derived orthotopic xenograft models (PDX), and human plasma samples. Exosomes were verified by electron microscopy, nanoparticle tracking analysis, and western blot. Cellular and exosome microRNAs from breast cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome microRNA expression was analyzed by qRT-PCR analysis. Results: Small RNA sequencing and qRT-PCR analysis showed that several microRNAs are selectively encapsulated or highly enriched in breast cancer exosomes. Importantly, the selectively enriched exosome microRNA, human miR-1246, was detected at significantly higher levels in exosomes isolated from PDX mouse plasma, indicating that tumor exosome microRNAs are released into the circulation and can serve as plasma biomarkers for breast cancer. This observation was extended to human plasma samples where miR-1246 and miR-21 were detected at significantly higher levels in the plasma exosomes of 16 breast cancer patients as compared to the plasma exosomes of healthy control subjects. Receiver Operating Characteristic (ROC) curve analysis indicated that the combination of plasma exosome miR-1246 and miR-21 levels is a better indicator of breast cancer than their individual levels. Conclusions: Our results demonstrate that certain microRNA species, such as miR-21 and miR-1246, are selectively enriched in human breast cancer exosomes and significantly elevated in the plasma of breast cancer patients. These findings indicate a potential new strategy to selectively analyze plasma breast cancer microRNAs indicative of the presence of breast cancer.