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Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer.

ABSTRACT: BACKGROUND:The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer. METHODS:An integrated unbiased approach was applied to derive a composite risk score for prognosis based on miRNA expression in primary breast tumors in 1051 breast cancer patients from The Cancer Genome Atlas (TCGA). Further analysis of the risk score with metastasis/recurrence was performed using the TCGA data set and validated in a separate patient population using small RNA sequencing. RESULTS:The three-miRNAs risk score (miR-19a, miR-93, and miR-106a) was developed using the TCGA cohort, which predicted poor prognosis (p?=?0.0005) independently of known clinical risk factors. The prognostic value was validated in another three following independent cohorts: GSE19536 (p?=?0.0009), GSE22220 (p?=?0.0003), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (p?=?0.0023). The three-miRNAs risk score predicted bone recurrence in TCGA (p?=?0.0052), and the findings were validated in another independent population of patients who experienced bone recurrence and age/stage-matched patients without any recurrence. The three-miRNAs risk score enriched multiple metastasis-related gene sets such as angiogenesis and epithelial mesenchymal transition in a gene-set-enrichment analysis. CONCLUSIONS:The authors developed the novel miRNA-based risk score, which is a promising biomarker for prediction of worse survival and bone recurrence potential in breast cancer.

SUBMITTER: Kawaguchi T

PROVIDER: S-EPMC6245576 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer.

Kawaguchi Tstutomu T Yan Li L Qi Qianya Q Peng Xuan X Edge Stephen B SB Young Jessica J Yao Song S Liu Song S Otsuji Eigo E Takabe Kazuaki K

Annals of surgical oncology 20181011 13

<h4>Background</h4>The use of biomarkers that allow early therapeutic intervention or intensive follow-up evaluation is expected to be a powerful means for reducing breast cancer mortality. MicroRNAs (miRNAs) are known to play major roles in cancer biology including metastasis. This study aimed to develop a novel miRNA risk score to predict patient survival and metastasis in breast cancer.<h4>Methods</h4>An integrated unbiased approach was applied to derive a composite risk score for prognosis b ...[more]

PMID: 30311168

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Project description:BackgroundCollagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. It was then found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors. However, the functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear.MethodsCTHRC1 expressions in breast cancer tissues and cells were assessed by qRT-PCR, western blot and immunohistochemistry. The relative expression level of miR-134, miR-155, miR-30c and miR-630 in breast cancer cells respectively was detected by qRT-PCR. Wild type (Wt) and Mutant type (Mut) CTHRC1 3'UTR sequences were cloned into a psi-CHECK2 reporter vector, and the relative luciferase activity was detected by dual-luciferase reporter assay in indicated cells. The effect of ectopic expression of miR-30c or gain and loss of CTHRC1 on cell viability, cell proliferation, cell cycle progression and apoptosis, cell invasion and migration was respectively detected by CCK-8 assay, colony formation assay, flow cytometry analysis, transwell invasion/migration assay. Protein levels of β-catenin, active β-catenin, normal and phosphorylated form of GSK-3β were detected by western blot in indicated cells. Immunofluorescence staining of β-catenin was performed to observe nuclear localization.ResultsWe found CTHRC1 was frequently up-regulated in human breast cancer cells and tissues. Then our cohort study and further meta-analysis validated high expression of CTHRC1 was associated with aggressive clinicopathological features and poor clinical outcome of breast cancer patients. In addition, CTHRC1 promoted cell proliferation, invasion and migration and suppressed cell apoptosis in breast cancer, which might be by activating GSK-3β/β-catenin signaling and inhibiting Bax/Caspase-9/Caspase-3 signaling respectively; and these biological functions of CTHRC1 could be directly negatively regulated by miR-30c.ConclusionTaken together, we identified the role of miR-30c/CTHRC1 axis in breast cancer progression and demonstrated CTHRC1 may serve as a prognostic biomarker and therapeutic target for breast cancer.

Dataset Information

Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer.

Publications

Novel MicroRNA-Based Risk Score Identified by Integrated Analyses to Predict Metastasis and Poor Prognosis in Breast Cancer.

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