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.

Highlights

  • Breast cancer is a heterogeneous disease; there are multiple subtypes with different molecular phenotypes, clinical features, and responses to treatment [1]

  • Co-precipitations performed in MDA-MB-231 cell lysates using the syndecan-binding protein (SDCBP)-specific antibody could pull-down c-src protein; control immunoprecipitations performed using IgG did not bind to SDCBP and precipitate csrc protein (Fig 2B and S2 Fig)

  • Immunoblots using the FLAG-tag antibody revealed a specific 32-kD protein band in the MDA-MB-231-SDCBP group; a specific band corresponding to the molecular weight of SDCBP with two missing PDZ domains was not observed in the MDA-MB-231-SDCBP-PDZ group (Fig 2C and S2 Fig), suggesting that c-src precipitated wild-type SDCBP but not SDCBP lacking the PDZ domains

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Summary

Introduction

Breast cancer is a heterogeneous disease; there are multiple subtypes with different molecular phenotypes, clinical features, and responses to treatment [1]. Classical immunopathological typing is mainly performed based on estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) expression. Triple negative breast cancer (TNBC) refers to breast cancers with negative ERα and PR expression and negative HER-2/Neu receptor overexpression [2]. A number of targeted therapeutic drugs for TNBC have been developed, chemotherapy remains as the only clinical option for TNBCs [5].

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