SRC Promotes Tamoxifen Resistance in Breast Cancer via Up-Regulating SIRT1
Jun Zhou1, Ming Xu1, Kehao Le1
1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.
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.
Insights
SRC and SIRT1 are elevated in tamoxifen-resistant breast cancer, correlating with poor patient survival. Targeting SRC and SIRT1 may offer new therapeutic strategies for overcoming tamoxifen resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endocrine therapy is crucial for estrogen receptor-positive breast cancer.
- Tamoxifen resistance presents a significant clinical challenge.
- Understanding resistance mechanisms is vital for developing new treatments.
Purpose of the Study:
- To investigate SRC and SIRT1 expression changes in tamoxifen-resistant breast cancer cells.
- To elucidate the functional roles of SRC and SIRT1 in tamoxifen resistance.
- To explore SRC and SIRT1 as potential therapeutic targets.
Main Methods:
- Gene expression analysis using RNA sequencing, qPCR, and Western blotting.
- In vitro and in vivo loss- and gain-of-function studies of SRC and SIRT1.
- Survival analysis using Kaplan-Meier and receiver operating characteristic curves.
Main Results:
- High SRC and/or SIRT1 expression is linked to poor survival in tamoxifen-treated patients.
- Down-regulating SRC or SIRT1 reversed tamoxifen resistance.
- SRC and SIRT1 inhibitors suppressed cancer cell proliferation.
- SRC overexpression promotes tamoxifen resistance, partly via up-regulating SIRT1.
Conclusions:
- SRC and SIRT1 are upregulated in tamoxifen-resistant breast cancer and associated with poor prognosis.
- SRC promotes tamoxifen resistance by upregulating SIRT1.
- SRC and SIRT1 represent potential therapeutic targets for tamoxifen-resistant breast cancer.
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