Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells

BMC Cancer

卷:21

Yoon Ho Ko¹  Heejin Lee¹  Ho Shik Kim²  Seo Yun Moon³  Keunsoo Kang⁴  Hee Yeon Lee⁵  Ji Hyung Hong⁵  Seoree Kim⁵  Sang Hoon Chun⁵  Hye Sung Won⁵ 

[1] Cancer Research Institute, College of Medicine, The Catholic University of Korea;

[2] Department of Biochemistry, College of Medicine, The Catholic University of Korea;

[3] Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea;

[4] Department of Microbiology, College of Natural Sciences, Dankook University;

[5] Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea;

关键词: Breast cancer;    Endocrine resistance;    Src;    Epidermal growth factor receptor;    Signal transducer and activator of transcription protein;   

DOI  :  10.1186/s12885-021-08641-7

来源: DOAJ

【 摘 要 】

Abstract Background The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. Methods The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. Results TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. Conclusions The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

【 授权许可】

Unknown