Abstract
Acquired resistance to tamoxifen remains a major obstacle in breast cancer (BC) treatment, since the underlying mechanism has not been fully elucidated. The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated and plays important roles in progression of breast cancer. In the present study, we aimed to investigate the biological role and clinical significance of UCA1 in BC drug resistance. Hence, we used quantitative PCR assay to evaluate the UCA1 expression in tissues from patients with BC as well as established tamoxifen-resistant BC cell lines in vitro. We tested the viability, invasive ability and apoptosis rate in MCF-7 and T47D cells using MTT assay, transwell assay and flow cytometry assay, respectively. The influence of UCA1 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/β-catenin signaling pathway was evaluated by immunofluorescence assay, western blot assay and luciferase reporter assay, respectively. We found that the expression of UCA1 positively correlated with the pathological grade and mortality of breast cancer patients, moreover, expressions of UCA1 was increased significantly in the tamoxifen-resistant cell lines compared with the wild type parental cells. Ectopic expression of UCA1 promoted cell survival and resistance to tamoxifen treatment, whereas inhibition of UCA1 enhanced tamoxifen sensitivity of BC cells and induced more apoptotic cells. In addition, tamoxifen-resistant cells exhibited increased Wnt signaling activation as measured by the TOP/FOP Wnt luciferase reporter assay and β-catenin protein level compared with parental MCF-7 and T47D cells, respectively. In line with these data, UCA1 depletion attenuated the activity of Wnt/β-catenin pathway activation and the tumorigenicity of the tamoxifen-resistant BC cells. Taken together, our data highlights the pivotal role of UCA1-Wnt/β-catenin signaling pathway in the tamoxifen resistance in breast cancer, which could be targeted to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer.
Highlights
Breast cancer is the most common female malignancy in the world and about 70% of them are estrogen receptor positive (ER+) [1]
Our result demonstrated that the expression of long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) was significantly higher in the stages III + IV group than that in the stage I + II group (p
In line with this, when we divided all 54 patients into two groups according to the median value of lncRNA UCA1 (Fig 1C), we found that the survival rate dropped in breast cancer patients with high expression level of lncRNA UCA1 when compared with those with low expression of UCA1 (Fig 1D)
Summary
Breast cancer is the most common female malignancy in the world and about 70% of them are estrogen receptor positive (ER+) [1]. An estrogen antagonist in the breast, is one of the standard hormone therapy for ER+ breast cancer in clinic. Intensive efforts have been made to overcome the acquired drug resistance leading to the identification of complex factors/pathways contributing to tamoxifen resistance including the growth factor receptor networks (EGFR/HER2), the NF-κB pathway as well as the contribution of cancer stem cells [1, 4, 5]. Further insights into the mechanisms underlying acquired tamoxifen resistance will help to improve the effectiveness and efficacy of ER+ breast cancer treatment with tamoxifen
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