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WNT Signaling in Disease
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Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling

1
School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
2
Wenzhou Institute of Biomaterials and Engineering, University of CAS, Wenzhou 325011, China
3
School of Biomedical Engineering, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou 325027, China
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(8), 892; https://doi.org/10.3390/cells8080892
Received: 22 July 2019 / Revised: 8 August 2019 / Accepted: 11 August 2019 / Published: 14 August 2019
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)
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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. View Full-Text
Keywords: breast cancer; XAV939; apoptosis; EMT; pristane; angiogenesis; combination treatment; Wnt signaling breast cancer; XAV939; apoptosis; EMT; pristane; angiogenesis; combination treatment; Wnt signaling
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Shetti, D.; Zhang, B.; Fan, C.; Mo, C.; Lee, B.H.; Wei, K. Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling. Cells 2019, 8, 892.

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