SHP-1 reverses trastuzumab resistance and migration in HER2-positive breast cancer cells through the stat3/p-stat3 pathway

Abstract

Decreased expression of Src homology region 2 domain containing protein tyrosine phosphatase 1 (SHP-1) was found in human breast cancer cell lines and primary breast cancers. As a candidate tumor suppressor gene, the role of SHP-1 in HER-2-positive breast cancer remains to be elucidated. The aim of the present study was to investigate the effects of upregulated SHP-1 expression in reversing trastuzumab resistance and migration by HER-2-positive breast cancer cells, potentially providing a new target to trastuzumab resistance in anti-HER2 therapy. Western blotting analysis was used to determine the expression levels of SHP-1 in trastuzumab-resistant cells transfected with a lentivirus vector expressing GFP-(control) or GFP-SHP-1 (experimental). MTT assay was used to determine changes in sensitivity to trastuzumab between two modified cell lines after overexpressing SHP-1. Clone formation and wound-healing assays were used to detect the capacity change in cell proliferation and migration. Western blot analysis was also used to examine the expressions of c-myc, cyclinD1, p-STAT3, STAT3, and MMP-9. Results from this study indicated that SHP-1 not only reduced cell proliferation and migration, but also significantly sensitized resistant cells to trastuzumab. Data also showed that SHP-1 restores sensitivity to trastuzumab in drug-resistant cell lines. Mechanistic analyses indicated that SHP-1 might target STAT3 to inactivate p-STAT3 and reduce expression of its downstream signaling pathway. In conclusion, results presented here suggest that targeting SHP-1 may represent a potential approach to re-sensitize previously resistant cells to trastuzumab treatment.