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.

• Authors: Xiao-Long Qian, Jun Zhang, Pei-Ze Li, Rong-Gang Lang, Wei-Dong Li, Hui Sun, Fang-Fang Liu, Xiao-Jing Guo, Feng Gu, Li Fu
• Journal: PloS one (PLoS One) Vol. 12 Issue 1 Pg. e0171169 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28141839 (Publication Type: Journal Article)

Chemical References

• SDCBP protein, human
• Syntenins
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human
• Dasatinib

Topics

• Animals
• CSK Tyrosine-Protein Kinase
• Carcinogenesis (drug effects, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dasatinib (administration & dosage, pharmacology)
• Disease Progression
• Female
• Humans
• Mice, Nude
• PDZ Domains
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Syntenins (chemistry, metabolism)
• Triple Negative Breast Neoplasms (metabolism, pathology)
• src-Family Kinases (metabolism)