Abstract
BackgroundTriple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Chemotherapy is still the standard of care for TNBC treatment. Circular RNAs (CircRNAs) have been recently discovered to be closely involved in the initiation and development of human cancers. Herein, we focus our attention on the functions and underlying mechanisms of circUBE2D2 in TNBC progression and chemoresistance.MethodsThe expression of circUBE2D2, miR-512-3p, and cell division cycle associated 3 (CDCA3) mRNA were determined by qRT-PCR. CCK-8, colony formation, transwell and flow cytometry assays were performed to detect cell proliferation, migration, invasion and apoptosis. Western blot assay was utilized to measure the protein level of CDCA3. RNA pull-down, luciferase reporter and RIP experiments were employed to examine the possible regulatory mechanism of circUBE2D2.ResultsCircUBE2D2 expression was elevated in TNBC tissues and cells. TNBC patients with high circUBE2D2 expression are inclined to present advanced TNM stage, lymph node metastasis and adverse prognosis. Knockdown of circUBE2D2 repressed cell proliferation, migration and invasion in vitro, and impeded tumor growth in vivo. Moreover, silencing of circUBE2D2 reduced doxorubicin resistance of TNBC cells. In-depth mechanism analysis revealed that circUBE2D2 served as a miRNA sponge to protect CDCA3 from the attack of miR-512-3p. Additionally, the tumor-suppressive effect induced by circUBE2D2 depletion was greatly impaired upon miR512-3p down-regulation or CDCA3 overexpression. Also, depletion of circUBE2D2 decreased the resistance to doxorubicin through regulating miR-512-3p/CDCA3 axis.ConclusionCircUBE2D2 promoted TNBC progression and doxorubicin resistance through acting as a sponge of miR-512-3p to up-regulate CDCA3 expression. Targeting circUBE2D2 combine with doxorubicin might be exploited as a novel therapy for TNBC.
Highlights
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis
CircUBE2D2 expression was up‐regulated in TNBC and correlated to a poor prognosis CircUBE2D2 expression was examined in 66 pairs of TNBC tumor tissues and neighboring non-cancerous tissues by qRT-PCR
The present study demonstrated that circUBE2D2 exerted an oncogenic role and induced doxorubicin resistance in TNBC through sponging miR-512-3p to up-regulate cell division cycle associated 3 (CDCA3) expression
Summary
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Dou et al Cancer Cell Int (2020) 20:454 cancer (TNBC) represents approximately 15–20% of all breast cancers that clinically are negative for the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) proteins [3]. Due to the aggressive behaviors, high risk of distant recurrence and lack of available targeted therapies, TNBC patients always carry a worse prognosis compared with other breast cancer subtypes [4]. More efforts need to be put into understanding the molecular mechanisms involved in the initiation, progression and chemoresistance of TNBC in order to overcome the drug resistance and improve the clinical outcome
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