Abstract
BackgroundTriple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20–30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients.MethodsThe miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student’s t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction.ResultsmiR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/β-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease.ConclusionsmiR-105/93-3p activates Wnt/β-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.
Highlights
Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics
Identification and validation of miRNAs associated with poor survival in TNBC In order to identify miRNAs that were associated with poor survival in TNBC, miRNA microarray profiles of 1299 patients were collected from the Metabric database [19, 23] and analyzed to examine differential expression between TNBC and non-TNBC breast cancer patients
The downstream effects on βcatenin activity are very similar in cells with miR-105 or miR-93-3p overexpression or silencing. These results suggest that miR-105 may operate through multiple mechanisms to activate Wnt/β-catenin signaling in TNBC. miR-105 was reported to serve as tumorsuppressive miRNAs in glioma by targeting SOX9 and SUZ12, as well as in hepatocellular carcinoma by targeting NCOA1 [35,36,37]
Summary
Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Neoadjuvant chemotherapy can result in a 20–30% pathologic complete response (pCR), TNBC patients have lower 3year overall survival rates compared with non-TNBC breast cancer patients [5]. The remaining 70–80% of TNBC patients have residual disease after neoadjuvant chemotherapy and suffer from the high risk of relapse and poor survival, especially in the first three years [5, 6]. Developing methods to improve the pCR rate in TNBC is currently a high priority, which will most likely require the identification of novel therapeutic targets. TNBC is often diagnosed late, with a high histological grade This late diagnosis is highly problematic because the 5-year survival rate is dramatically decreased from stage II (76%) to stage III (45%) cancers [7]. Along with novel target discovery, identification, and development of early detection biomarkers for TNBC is another critical undertaking
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