SRC Promotes Tamoxifen Resistance in Breast Cancer via Up-Regulating SIRT1

Background: Endocrine therapy plays a key role in estrogen receptor-positive breast cancer patients; but, tamoxifen resistance could be a real difficulty for these patients. Several attempts have been made to explore the mechanism and new therapies for these patients. We intend to clarify the expression change of SRC and SIRT1 in tamoxifen-resistant breast cancer cells and explore their functions on tamoxifen resistance. Methods: SRC and SIRT1 expressions were analyzed by RNA sequencing, qPCR and Western blotting. Loss and gain of function of SRC and SIRT1 were utilized to indicate their oncogenic roles in tamoxifen resistance in vitro and in vivo. Kaplan-Meier analysis and receiver operating characteristic curve were used to evaluate the survival and the predicted effects of SRC and SIRT1 on patients' prognosis. Results: High expressions of SRC and/or SIRT1 were found in tamoxifen-resistant cells and related to poor overall survival (p<0.05 for SRC, p<0.001 for SIRT1, p<0.001 for SRC and SIRT1) and cancer-specific survival (p<0.05 for SRC, p<0.01 for SIRT1, p<0.01 for SRC and SIRT1) of tamoxifen-treated breast cancer patients. Down-regulation of SRC (p<0.01) or SIRT1 (p<0.05) separately reversed the resistance to tamoxifen and the minimal concentration of SRC inhibitor KX-01 (p<0.05) or SIRT1 inhibitor EX527 (p<0.001) could also suppress cell proliferation. The expression level of SIRT1 was positively correlated with that of SRC. Overexpression of SRC significantly promotes the cell resistance to tamoxifen inhibited by SIRT1 (p<0.01). In vivo experiments confirmed the effects of SRC on tumor growth by over- or down-regulating SRC expression (p<0.001 and p<0.001, respectively). Conclusion: SRC and SIRT1 are both up-regulated in tamoxifen-resistant breast cancer cells and related to a poor prognosis in tamoxifen-treated breast cancer. Moreover, SRC could promote tamoxifen resistance by up-regulating SIRT1. SRC and SIRT1 might be novel therapeutic targets in tamoxifen-resistant breast cancer and the interaction between SRC and SIRT1 needs to be further explored.