c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

Abstract

Oncogene c‐Src has been found to be a potential target for the treatment of triple‐negative breast cancer (TNBC). However, the therapeutic effects of the c‐Src inhibitor on TNBC patients are controversial compared to those on cell lines. The molecular mechanisms of the inhibitory effects of the c‐Src inhibitor on TNBC remain unclear. Herein, we showed that a specific c‐Src inhibitor, PP2, was effective in inhibiting phosphorylation of c‐Src in 4 cell lines: T‐47D, SK‐BR‐3, SUM1315MO2, and MDA‐MB‐231, regardless of hormone receptors and human epidermal growth factor receptor 2 (HER2) expression levels. Giving PP2 preferentially reduced the S phase of cell cycles and inhibited colony formation in SUM1315MO2 and MDA‐MB‐231, but not in SK‐BR‐3 and T‐47D cells. Furthermore, PP2 effectively blocked cell migration/invasion and epithelial‐mesenchymal transition (EMT) in TNBC cell lines, SUM1315MO2 and MDA‐MB‐231. An EMT biomarker, vimentin, was highly expressed in 2 TNBC cell lines when they were compared with SK‐BR‐3 and T‐47D cells. Further depletion of vimentin by shRNA remarkably attenuated the inhibitory effects of the c‐Src inhibitor on TNBC cells in vitro and in vivo, indicating a crucial action of vimentin to affect the function of c‐Src in TNBC. This study provides an important rationale for the clinic to precisely select TNBC patients who would benefit from c‐Src inhibitor treatment. This finding suggests that traditional markers for TNBC are not sufficient to precisely define this aggressive type of cancer. Vimentin is identified as an important biomarker to enable categorization of TNBC.

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

“…Src inhibitor PP2 reduced the S phase of cell cycles and inhibited colony formation, blocked cell migration/invasion and EMT in triple-negative breast cancer cell lines. Vimentin expression in this study was suggested as a potential biomarker to identify responsive cancer cell populations associated with an EMT phenotype [65]. The mesenchymal transition in breast cancer could be stimulated by different mechanisms, and it has been widely cited as an effective event associated with the promotion ability of Src in breast cancer.…”

c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

“…The high expression of Estrogen Receptor (ERα) and HER2 were firstly reported as favorable indicators for the use of c-Src inhibitors in breast cancer cell lines [ 75 , 76 ]. Recently, it has been reported that triple negative breast cancer (TNBC) cells also showed sensitivity to c-Src inhibitors [ 79 ]. Lou and colleagues reported that c-Src inhibitors were able to prevent TNBC invasive ability by determining a significant decrease in vimentin expression.…”

“…Lou and colleagues reported that c-Src inhibitors were able to prevent TNBC invasive ability by determining a significant decrease in vimentin expression. Thus, authors suggested vimentin as a predictive biomarker to stratify breast cancer patients in clinical trials testing c-Src inhibitors [ 79 ].…”

The LQB-223 Compound Modulates Antiapoptotic Proteins and Impairs Breast Cancer Cell Growth and Migration

“…Although some studies have shown that vimentin expression is a marker for poor prognosis [36], others have reported that its high expression can sensitize triple-negative breast cancer in vitro and in vivo to the c-Src inhibitor (dasatinib) [37,38]. Moreover, depletion of vimentin mitigates the c-Src inhibitory effects, suggesting that vimentin plays a role in the regulation of c-Src [38,39]. In line with our findings showing that LQB-223 reduced cell migration, treatment with LQB-223 reduced mRNA levels of KRT18 and increased CLDN3 .…”