Abstract
Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial–mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.
Highlights
Breast cancer (BC) is the second most common cancer in the world and is the fifth leading cause of cancer death among women[1]
In order to identify the miRNA expression profile in BC, total RNAs from 422 breast cancer specimens and 31 noncancerous breast tissues obtained from Sun Yat-Sen University Cancer Center (SYSUCC) were detected using our custom miRNA microarray containing 1849 probes[20]
The result showed that 399 of the probed 1849 miRNAs were differentially expressed between BC and noncancerous tissues, in which 193 miRNAs were upregulated and 206 downregulated in BC tissues
Summary
Breast cancer (BC) is the second most common cancer in the world and is the fifth leading cause of cancer death among women[1]. Official journal of the Cell Death Differentiation Association. Zhao et al Cell Death and Disease (2019)10:479 identification of novel biomarkers for prediction and therapeutic targets for treatment of metastasis in BC patients. MicroRNAs (miRNAs) are a class of noncoding RNAs of about 22 nucleotides in length that negatively regulate posttranscriptional gene expression by either repressing the targeted mRNA translation or degrading the mRNAs via partly binding to mRNA’s 3′ untranslated region (UTR)[6]. Studies show that the abnormally expressed miRNAs are involved in breast tumorigenesis and metastasis by acting as a tumor suppressor or tumor activator[7,8,9,10]. The role and mechanism of miRNA in BC still have not been fully elucidated[11,12,13]
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