Abstract
MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. cDNA microarray data revealed that differentially expressed genes when miR-671-5p was transfected are associated with cell proliferation, invasion, cell cycle, and EMT. These data indicate that miR-671-5p functions as a tumor suppressor miRNA in breast cancer by directly targeting FOXM1. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management.
Highlights
The human genome is composed of approximately 1.5% protein-coding genes, with the rest being non-coding [1]
Downregulation of miR-671-5p expression was present in 21 of 30 (70%) invasive ductal carcinoma (IDC) compared with their adjacent tissues (p < 0.05), which includes 8 of triple negative breast cancer (TNBC) (80%) and of 20 (60%) non-TNBCs (Figure 1)
We report a previously undescribed mechanism for the tumor suppressor role of miR-671-5p in breast cancer
Summary
The human genome is composed of approximately 1.5% protein-coding genes, with the rest being non-coding [1]. MicroRNAs (miRNAs) are a class of evolutionary conserved, noncoding RNAs, 18–25 nucleotides in length, that regulate gene expression by annealing to their complementary sites on coding sequences (CDS) or 3′ untranslated regions (UTRs) of target genes [2]. The commonly accepted model of human breast cancer proposes a linear multistep process which initiates as flat epithelial atypia (FEA), progresses to atypical ductal hyperplasia (ADH), evolves into ductal carcinoma in situ (DCIS), and culminates in the potentially lethal stage of invasive ductal carcinoma (IDC) [8]. This linear model of breast cancer progression has been the rationale for detection methods such as mammography in hopes of diagnosing and treating breast cancer at earlier clinical stages [9]. TNBC is known as ER-negative, PR-negative, and HER- 2 negative subtype of breast cancer, which is insensitive to some of the most effective therapies available for breast cancer treatment including HER2 and endocrine therapies
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