Therapeutic Study Of Low Dose Paclitaxel Combined With XAV939 On Triple Negative Breast Cancer

Breast cancer is the second most common type of cancer only after lung cancer.It is one of the major leading causes of death in women.Triple-negative breast cancer(TNBC)is aggressive type of breast cancer accounting for 15%of overall breast cancer.Angiogenesis and Metastasis is major hallmark in breast cancer and in TNBC it is highly aggressive due to lack of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2 receptor).Wnt signaling pathway play important role in cellular progression Dysregulation in Wnt signalling contributes for aggressive progression and metastasis in TNBC.XAV939 is a tankyrase inhibitor,which play important role in Wnt signalling Treatment with XAV939 alone does not inhibit TNBC significantly.In this study,we used a strategy of combination of low dose paclitaxel with Wnt signaling inhibitor(XAV939)for targeted treatment of TNBC cancer.The current study examined the effect of the paclitaxel-combined with XAV939 treatment on diverse breast cancer cell lines and also on MDA-MB-231 xenograft mice model considering the various aspect such as angiogenesis and metastasis The MTT,cell migration and invasion assay indicated that combination of paclitaxel(20 nM)and XAV939(10 LM)prompted cytotoxicity effect on various breast cancer cell line including MDA-MB-231,MDA-MB-468,BT549,MCF-7,and T-47D cell lines.Whereas,combination drug inhibited migratory and invasion property of MDA-MB-231 cells.The paclitaxel-combined XAV939 treatment caused apoptosis in MDA-MB-231 and MCF 7 cells by modulating apoptotic protein.The BCL-2 expression was supressed and cleavage of caspases-3 and PARP was increased in MDA-MB-231 cells and MCF-7 cells.The similar result was also observed in the tumor sample of MDA-MB-231 xenograft mice model.Furthermore,western blot result,RT-PCR result and immunohistochemistry images indicated that the paclitaxel-combined XAV939 treatment inhibited epithelial-mesenchymal transition(EMT)markers and angiogenesis marker at mRNA and protein level by supressing the expression ofβ-catenin.External carcinogen such as pristane induced breast tumor was supressed significantly by our combination treatment.For the first time,we showed that combining low dose of paclitaxel with Wnt inhibitor(XAV939)can significantly cure the TNBC and external carcinogen-induced breast cancer.Overall,data confirmed that paclitaxel-combined XAV939 regimen was found to supress Wnt signalling and induce apoptosis,resulting in the suppression of EMT and angiogenesis.