Triple negative breast cancer (TNBC) is an aggressive cancer and its prognosis remains poor. Combinational therapies are a promising strategy for enhancing treatment efficacy. Blockade of STAT3 signaling have been shown to enhance the response of cancer cells to conventional chemotherapeutic agents. Here we used a SHP-1 agonist SC-43 to dephosphorylate STAT3, thereby suppressing oncogenic STAT3 signaling, and tested it in combination with docetaxel in TNBC cells.
TNBC cell lines (HCC-1937, MDA-MB-468, MDA-MB-231) were used for in vitro studies. Cell viability was examined by MTT assay. Combination index was determined using Calcusyn anaysis. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of SC-43 in combination with docetaxel was tested in nude mice with breast cancer xenografts.
To exam expression of SHP-1 in clinical samples, we analyzed mRNA expression of SHP-1 gene (ptpn6) in a public TNBC dataset (The Cancer Genome Atlas, TCGA). We found that higher SHP-1 mRNA expression is associated with better overall survival in TNBC patients. Sequential combination of docetaxel and SC-43 in vitroshowed enhanced anti-proliferation and apoptosis associated with decreased p-STAT3 and decreased STAT3-downstream effector cyclin D1 in the TNBC cell lines MDA-MB-231, MDA-MB-468 and HCC-1937. Ectopic expression of STAT3 reduced theincreased cytotoxicity induced by the combination therapy. In addition, this sequential combination showed enhanced SHP-1 activity compared to SC-43 alone. Furthermore, siRNA against SHP-1 reduced apoptosis induced by the combination treatment. Moreover, by ectopic expression of SHP-1 mutants that caused SC-43 to lose its SHP-1 agonist capability, the SC-43-induced p-STAT3 signaling inhibition was reduced in the cells subjected to the combination treatment, suggesting SHP-1 plays a crucial role in docetaxel-SC-43-mediated TNBC cell apoptosis, Importantly, combination of docetaxel and SC-43 showed enhanced anti-tumor growth compared to single-agent therapy in MDA-MB-231 xenografted tumor mice.
SHP-1 agonist SC-43 enhanced the anti-tumor effect of docetaxel by SHP-1 dependent STAT3 inhibition in human TNBC cells. We suggest a therapeutic potential of SHP-1 agonist in combination with docetaxel for TNBC.
Clinical trial identification
Legal entity responsible for the study
National Taiwan University Hospital
All authors have declared no conflicts of interest.