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      Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer

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          Abstract

          Introduction

          MicroRNAs (miRs) are interesting new diagnostic targets that may provide important insights into the molecular pathogenesis of breast cancer. Here we evaluated, for the first time, the feasibility and clinical utility of circulating miRs as biomarkers for the detection and staging of breast cancer.

          Methods

          The relative concentrations of breast cancer-associated miR10b, miR34a, miR141 and miR155 were measured in the blood serum of 89 patients with primary breast cancer (M0, n = 59) and metastatic disease (M1, n = 30), and 29 healthy women by a TaqMan MicroRNA Assay.

          Results

          The relative concentrations of total RNA ( P = 0.0001) and miR155 ( P = 0.0001) in serum significantly discriminated M0-patients from healthy women, whereas miR10b ( P = 0.005), miR34a ( P = 0.001) and miR155 ( P = 0.008) discriminated M1-patients from healthy controls. In breast cancer patients, the changes in the levels of total RNA ( P = 0.0001), miR10b ( P = 0.01), miR34a ( P = 0.003) and miR155 ( P = 0.002) correlated with the presence of overt metastases. Within the M0-cohort, patients at advanced tumor stages (pT3 to 4) had significantly more total RNA ( P = 0.0001) and miR34a ( P = 0.01) in their blood than patients at early tumor stages (pT1 to 2).

          Conclusions

          This pilot study provides first evidence that tumor-associated circulating miRs are elevated in the blood of breast cancer patients and associated with tumor progression.

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          Most cited references13

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          Dicer is essential for mouse development.

          To address the biological function of RNA interference (RNAi)-related pathways in mammals, we disrupted the gene Dicer1 in mice. Loss of Dicer1 lead to lethality early in development, with Dicer1-null embryos depleted of stem cells. Coupled with our inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggests a role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development.
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            Circulating nucleic acids (CNAs) and cancer--a survey.

            It has been known for decades that it is possible to detect small amounts of extracellular nucleic acids in plasma and serum of healthy and diseased human beings. The unequivocal proof that part of these circulating nucleic acids (CNAs) is of tumor origin, initiated a surge of studies which confirmed and extended the original observations. In the past few years many experiments showed that tumor-associated alterations can be detected at the DNA and RNA level. At the DNA level the detection of point mutations, microsatellite alterations, chromosomal alterations, i.e. inversion and deletion, and hypermethylation of promoter sequences were demonstrated. At the RNA level the overexpression of tumor-associated genes was shown. These observations laid the foundation for the development of assays for an early detection of cancer as well as for other clinical means.
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              MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA.

              Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.
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                Author and article information

                Journal
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central
                1465-5411
                1465-542X
                2010
                3 November 2010
                : 12
                : 6
                : R90
                Affiliations
                [1 ]Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
                [2 ]First Department of Obstetrics and Gynecology, Ludwig Maximilians University of Munich, Munich, Germany
                [3 ]Clinic of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [4 ]Clinic of Gynecology, Heinrich Heine University, Düsseldorf, Germany
                Article
                bcr2766
                10.1186/bcr2766
                3046429
                21047409
                8037e4e4-532f-47a5-817a-ca12c91c1d15
                Copyright ©2010 Roth et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 May 2010
                : 14 October 2010
                : 3 November 2010
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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