Abstract
MicroRNAs (miRNAs) have critical roles in regulating cancer cell survival, proliferation and sensitivity to chemotherapy. The potential application of using miRNAs to predict chemotherapeutic response to cancer treatment is highly promising. However, the underlying mechanisms of chemotherapy response control by miRNAs remain to be fully identified and their prognostic value has not been fully evaluated. Here we show a strong correlation between miR-205 expression and chemosensitivtiy to TAC (docetaxol, doxorubicin plus cyclophosphamide), a widely-used neoadjuvant chemotherapy (NAC) regimen, for breast cancer patients. High level of miR-205 predicted better response to TAC regimen NAC in breast cancer patients. We found miR-205 downregulated in both MCF-7/A02 and CALDOX cells, two drug-resistant derivatives of MCF-7 and Cal51 cells, and its ectopic expression led to an increase in apoptosis resensitization of both drug-resistant cell lines to doxorubicin and taxol. We further show that miR-205 directly binds VEGFA and FGF2 mRNA 3′-UTRs and confirm that miR-205 levels are negatively correlated with VEGFA and FGF2 mRNA expression in breast cancer patients. Adding VEGFA and FGF2 exogenously to chemosensitive breast cancer cells and chemoresistant cells with miR-205 overexpression led to drug resistance. Consistently, low VEGFA and FGF2 expression correlated with better response to NAC in breast cancer patients. In addition, inhibition of tumor growth and resensitization to doxorubicin were also observed in mouse tumor xenografts from cells overexpressing miR-205. Taken together, our data suggest that miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis. MiR-205 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.
Highlights
Despite the progress in early diagnosis, breast cancer remains the most common cancer in women worldwide.[1]
We show that miR-205 expression levels might be useful for predicting response to TAC regimen as Neoadjuvant chemotherapy (NAC) treatment in breast cancer patients
It is well established that miRNAs can function as tumor suppressors or oncogenes depending on the cellular context and cancer types.[42,43] miR-205 is located in chromosome 1q32.2 and its expression pattern mirrors that of the miR-200 family.[44,45] miR-205 is upregulated in the progenitor subpopulation of a mouse mammary epithelial cell line, promoting cell proliferation and tumor initiation through targeting PTEN.[46]
Summary
Despite the progress in early diagnosis, breast cancer remains the most common cancer in women worldwide.[1]. MicroRNAs (miRNAs), a class of highly conserved, short, non-protein-coding RNAs that negatively regulate gene expression, have emerged as crucial regulators of the drug response by modulating dug efflux, cell apoptosis, epithelial– mesenchymal transition (EMT) and cancer stem cells.[8,9,10] Previous studies have revealed that numerous miRNAs are upregulated or downregulated in breast cancer, contributing to the initiation and development of the disease, as well as its drug sensitivity.[11,12,13] For instance, overexpression of miRNA-451 sensitizes breast cancer cells to doxorubicin,[14] and upregulation of miRNA-21 is associated with acquired trastuzumab resistance.[15] we have recently reported that the miR-106b-93-25 cluster leads to activation of EMT transition and resistance to doxorubicin and taxol.[16,17] predictive miRNA signatures of NAC response remain to be found and fully validated.
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