Abstract
Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.
Highlights
Breast cancer is endocrine-related cancer with high incidence and mortality rates in women worldwide
We aimed to examine a potential therapeutic effect of a low dose of paclitaxel combined with XAV939 on various breast cancer lines (MDA-MB-231, MDA-MB 468, BT549, MCF-7, and T-47D), MDA-MB-231-xenografted mice, and pristane-induced breast tumor
These results suggest that each single treatment of paclitaxel (20 nM) or XAV939 (10 μM) partially affected the Wnt signaling pathway and apoptotic process in MDA-MB-231 and MCF-7, whereas the combination treatment was actively involved in inhibiting the Wnt signaling pathway and inducing apoptosis
Summary
Breast cancer is endocrine-related cancer with high incidence and mortality rates in women worldwide. The incidence rate of breast cancer has increased continuously. Cells 2019, 8, 892 despite an advance in early detection techniques and an awareness of breast cancer. Based on the molecular subtype, four different types of breast cancer have been identified: (1) Luminal A (HR+/HER2−) (71%), (2) luminal B (HR+/HER2+) (12%), (3) HER2-enriched (HR-/HER2+) (5%), and (4) triple-negative (HR−/HER2−) (12%) [1]. Triple-negative breast cancer (TNBC) is responsible for. The tendency of TNBC to metastasize to distinct organs is higher compared to other cancer phenotypes. TNBC is more sensitive to chemotherapy compared to other types of breast cancer. Even after a series of therapies (a traditional radiotherapy, an adjuvant chemotherapy, a systematic therapy, and a targeted therapy), the peak risk of TNBC recurrence takes place within 3–5 years, leading to death in most of the cases [5,6]. To ease the burden of TNBC treatment, an optimal therapeutic approach should be found
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