Abstract
The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.
Highlights
Breast cancer is currently the leading type of malignancy among the female population worldwide
Considering that the presence of cytoplasmic vacuolization has been discussed in certain types of cell death[26] and FTY720 did induce apoptosis of mouse breast cancer cells[17], we examined proteins involved in apoptosis and autophagy
The present study demonstrated that FTY720 could overcome resistance to trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells
Summary
Breast cancer is currently the leading type of malignancy among the female population worldwide. One phase 3 study demonstrated that adding everolimus to second-line treatment significantly prolonged progression-free survival of patients with HER2-positive breast c ancer[13], the adverse effects of this combination therapy limited its adoption into general practice. FTY720 in the combination with tamoxifen may overcome resistance in hormonal therapy-resistant breast cancer by inhibiting sphingosine-1-phosphate receptors or mimicking histone deacetylase inhibitors[18,19]. Together with epidermal growth factor receptor kinase inhibitors, FTY720 has shown its potential effects in inhibiting the growth of basal-like breast cancer c ells[20]. Despite showing promising effects in the treatment of breast cancer, the role of FTY720 in resistance to HER2-targeted therapies has yet to be investigated. This study hypothesized that FTY720 can inhibit the proliferation of trastuzumab-resistant breast cancer cells through its multipotent anti-cancer effects. We confirmed the efficacy of FTY720 in vivo using a heterotopic xenograft mouse model
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