Abstract
More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.
Highlights
Breast cancer is the most frequently occurring cancer, ranking no. 1 in women worldwide[1]
The majority of the differentially expressed circRNAs were spliced from gene exons (Supplementary Table 2) data for which are presented as distinct expression clusters (Fig. 1d)
Several studies reported that circRNAs are associated with cell cycle in breast cancer[17,38] and with tight junctions, antigen presentation, and mTOR signaling pathways in TNBC34
Summary
Breast cancer is the most frequently occurring cancer, ranking no. 1 in women worldwide[1]. Breast cancer is a complex and heterogeneous disease characterized by different molecular alterations[2]. At least five independent intrinsic molecular subtypes [luminal A (LA), luminal B (LB), Her-2 overexpressed, triple-negative breast cancer (TNBC), and normal breast-like] have been consistently reported in different cohorts[3,4]. Therapeutic improvements, and prolonged survival over the last few decades, many patients with breast cancer cannot escape eventual recurrence, metastasis, and chemoresistance. This highlights the need to unravel yet unknown biomarkers as well as the underlying mechanisms for breast cancer malignancy
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