Abstract
Background: Chemotherapy failure causes high breast cancer recurrence and poor patient prognosis. Thus, we studied a cohort of novel biomarkers to predict chemotherapeutic response in breast cancer. In this study, miRNA expression profiling was performed on 10 breast cancer punctured specimens sensitive to chemotherapy (MP grade 4, 5) and 10 chemotherapy resistant (MP grade 1). Differentially expressed miRNAs were verified by qRT-PCR in 60 initial samples, 59 validated samples and 71 independent samples. A miRNA signature was generated using a Logistic regression model. A receiver operating characteristic (ROC) test was used to assess specificity and sensitivity of single miRNA and miRNA signature. Target genes regulated by miRNAs and their involved signaling pathways were analyzed using GO enrichment and KEGG software. MiRNAs expression were separately compared with ER, PR, HER2 immunohistochemical staining and different drugs. qRT-PCR showed that the high expression of miR-23a-3p, miR-200c-3p, miR-214-3p and the low expression of miR-451a and miR-638 were closely related to chemoresistance. According to the formula for calculating the drug resistance risk, patients in the high-risk group were more likely to develop chemotherapy resistance than the low-risk group. Bioinformatics analysis showed that 5 miRNAs and target genes are mainly involved in p53, ubiquitin-mediated proteolysis, mTOR, Wnt, cells skeletal protein regulation, cell adhesion and ErbB signaling pathways. miR-451a expression was associated with ER, HER-2 status and anthracyclines. A miRNA signature of chemotherapeutic response may be clinically valuable for improving current chemotherapy regimens of individual treatment for patients with breast cancer.
Highlights
According to the American Cancer Society, 244,660 breast cancer cases of women were estimated in 2016, and of these almost 40,450 people died from these cancers [1]
Excluding those with PCR primers unavailable temporarily for validation or with low signal value in the miRNA microarray, we selected 6 miRNAs: miR-200c-3p, miR-214-3p, miR-23a-3p, and miR-23b3p, miR-451a and miR-638 for subsequent validation by qRT-PCR in the training set (N 60). qRT-PCR results confirmed six miRNAs were significantly associated with chemoresistance (p < 0.05; FC > 1.5), which conclusion was the same as the microarray data
Of these six miRNAs, expression of miR-200c-3p, miR-214-3p, miR23a-3p, and miR-23b-3p were positively associated with chemoresistance, and expression of miR-451a and miR-638 were negatively associated with chemoresistance (Figure 1D)
Summary
According to the American Cancer Society, 244,660 breast cancer cases of women were estimated in 2016, and of these almost 40,450 people died from these cancers [1]. Surgery and chemotherapy are chief firstline therapies for breast cancer [2], but high recurrence and metastasis reduce the patients’ survival attributing to poor chemotherapeutic effect. Pathology & Oncology Research miRNA Signature of Chemotherapy Response. Chemotherapy failure causes high breast cancer recurrence and poor patient prognosis. We studied a cohort of novel biomarkers to predict chemotherapeutic response in breast cancer. MiRNA expression profiling was performed on 10 breast cancer punctured specimens sensitive to chemotherapy (MP grade 4, 5) and 10 chemotherapy resistant (MP grade 1). According to the formula for calculating the drug resistance risk, patients in the high-risk group were more likely to develop chemotherapy resistance than the low-risk group. A miRNA signature of chemotherapeutic response may be clinically valuable for improving current chemotherapy regimens of individual treatment for patients with breast cancer
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