Abstract
BackgroundTriple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target. Here we screened differentially expressed lncRNAs through bioinformatics analysis and identified CARMN as a downregulated lncRNA which is lowest expressed in TNBC. We aimed to identify the potential role and molecular mechanisms of CARMN in TNBC.MethodsPredictive value of CARMN was explored in breast cancer cohorts. TNBC cell lines with CARMN overexpression or CARMN silence and were used for in vitro and in vivo experiments. RNA-seq of CARMN overexpressed cells was performed for exploring downstream of CARMN.ResultsCARMN is downregulated at different phase of malignant transformation of breast tissue. CARMN can predict both better prognosis and higher response rate of cisplatin-based neoadjuvant chemotherapy in breast cancer. A nomogram is built to predict cisplatin-based chemotherapy response in breast cancer. Through in vitro and in vivo studies, we confirmed CARMN can also inhibit tumorigenesis and enhance sensitivity to cisplatin in TNBC cells. RNA-seq and further experiments revealed CARMN can inhibit DNA replication. MCM5, an important DNA replication initiation factor, is the most downregulated gene in DNA replication pathway following CARMN overexpression. We confirmed CARMN can produce miR143-3p from its exon5 which is DROSHA and DICER dependent, resulting binding and decrease of MCM5. Moreover, suppressing miR143-3p can weaken function of CARMN in suppressing tumorigenesis and promoting chemosensitivity.ConclusionsOur results indicated lncRNA CARMN is a predictive biomarker of better prognosis and enhanced cisplatin sensitivity in TNBC. CARMN is the host gene of miR143-3p which downregulates MCM5, causing inhibited DNA replication.
Highlights
Triple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target
LncRNA Cardiac Mesoderm Enhancer-associated Noncoding RNA (CARMN) is a biomarker for prognosis and malignant transformation in breast cancer Differentially expressed long non-coding RNAs (lncRNAs) between breast cancer and normal breast tissues were screened from The Cancer Genome Atlas (TCGA) dataset, GSE45827, GSE31192, GSE3744 and GSE21422 (FDR < 0.05, |log2FC| > 2)
Decrease of CARMN in breast cancers samples comparing with paired normal tissues was confirmed in two cohorts (Fig. 1B, C, Figure S1A) with outstanding capability in discriminating tumor from normal tissue evaluated by Receiver operating characteristic (ROC) curve (Figure S1B)
Summary
Triple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target. We screened differentially expressed lncRNAs through bioinformatics analysis and identified CARMN as a downregulated lncRNA which is lowest expressed in TNBC. We aimed to identify the potential role and molecular mechanisms of CARMN in TNBC. Compared with other subtypes of breast cancer, TNBC is more likely to appear in young patients, with the worst prognosis due to its high capability of invasion, heterogeneous behavior and lack of effective treatment target [1]. Increasing sensitivity of existed chemotherapy regimens and exploring novel therapeutic targets to improve the overall prognosis for TNBC are of urgent. Molecular mechanism for lncRNAs regulating TNBC progression and chemotherapy resistance are still not fully understood. CARMN’s role in breast cancer has never been reported
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