Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP)

Abstract

Triple negative breast cancer (TNBC) progresses rapidly but lacks effective targeted therapies. Our previous study showed that downregulating syndecan-binding protein (SDCBP) in TNBC inhibits the proliferation of TNBC cells. Dasatinib is a new small-molecule inhibitor of c-src phosphorylation. The aim of this study was to investigate if SDCBP is a potential marker to indicate whether a TNBC is suitable for dasatinib therapy. This study applied co-immunoprecipitation to identify the interaction between SDCBP and c-src in TNBC cell lines. In addition, immunohistochemistry was used to investigate SDCBP and tyrosine-419 phosphorylated c-src (p-c-src-Y419) expression in TNBC tissues. SDCBP-overexpressing MDA-MB-231 cells were then constructed to evaluate the effects of dasatinib on SDCBP-induced TNBC progression in vitro and tumor formation in nude mice. We found wild-type SDCBP interacted with c-src and promoted the phosphorylation of c-src; this phosphorylation was completely blocked by dasatinib. SDCBP lacking the PDZ domain had no such effect. Among the 52 consecutive random TNBC cases examined, the expression of SDCBP was consistent with that of p-c-src-Y419, and positively correlated with histological grading or Ki-67 levels. SDCBP overexpression significantly accelerated the proliferation and cell cycle progression of the TNBC cell line MDA-MB-231; these effects were prevented by dasatinib treatment. However, the subsequent inhibition of p27 expression partially restored the proliferation and viability of the TNBC cells. The results of this study suggest that SDCBP interacts with c-src, regulates G1/S in TNBC cells, and enhances tumor cell proliferation by promoting the tyrosine phosphorylation of c-src at residue 419. Dasatinib inhibits such phosphorylation and blocks SDCBP-induced cell cycle progression. Therefore, SDCBP might be an important marker for identifying TNBC cases that are suitable for dasatinib therapy.

Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen

“…This may partly explain why SDCBP silencing alone did not alter the levels of p21 and p27, while these levels were changed with tamoxifen. We also predicted that p21 levels depend more on the estrogen pathway than on SDCBP in ER-positive BCa cells; however, p27 levels may be closely related to the interaction between SDCBP and c-src as previously reported in triple-negative breast cancer cells 24 . In addition, SDCBP silencing enhances the effects of tamoxifen and may be useful as a targeted treatment in ER-positive BCa.…”

“…SDCBP-overexpressing and control cell lines were constructed as described previously 24 . Corresponding exogenous protein overexpression was evaluated by Western blot after the cells were cultured for 8 and 6 weeks for MCF-7 and T47D cells, respectively, in the appropriate medium containing 0.5 mg/mL of G418 (Sigma-Aldrich).…”

Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis

“…DBA/1 mice were boosted with an injection of chicken CII emulsified in IFA on the 21st day. Mice in the dasatinib group received 10 mg/kg (20, 21) dasatinib from the day 26 to 57 orally once a day. Mice in the vehicle group received the same volume of citrate buffer (pH 3.1) at the same times.…”

Trastuzumab-Targeted Biodegradable Nanoparticles for Enhanced Delivery of Dasatinib in HER2+ Metastasic Breast Cancer

“…For instance, SRC has been implicated in the development of resistance to the anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab (TAB) in HER2 positive breast cancer. In this context, inhibition of SRC with DAS has shown preclinical and clinical activity [10][11][12][13].…”