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

Author

Seo Yun Moon, Heejin Lee, Seoree Kim, Ji Hyung Hong, Sang Hoon Chun, Hee Yeon Lee, Keunsoo Kang, Ho Shik Kim, Hye Sung Won, and Yoon Ho Ko

Subjects
Breast cancer, Endocrine resistance, Src, Epidermal growth factor receptor, Signal transducer and activator of transcription protein, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

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.

Published
2021
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2. Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells

Author

Sang Hoon Chun, Ji Hyung Hong, Keunsoo Kang, Heejin Lee, Seoree Kim, Hye Sung Won, Ho Shik Kim, Yoon Ho Ko, Hee Yeon Lee, and Seo Yun Moon

Subjects
STAT3 Transcription Factor, Cancer Research, Antineoplastic Agents, Hormonal, Estrogen receptor, Apoptosis, Breast Neoplasms, Breast cancer, Cell Movement, Tumor Cells, Cultured, Genetics, medicine, Humans, Viability assay, skin and connective tissue diseases, RC254-282, Cell Proliferation, Signal transducer and activator of transcription protein, Chemistry, Cell growth, Epidermal growth factor receptor, Cell Cycle, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell cycle, Cyclic S-Oxides, Gene Expression Regulation, Neoplastic, Dasatinib, Tamoxifen, Oncology, Drug Resistance, Neoplasm, Cell culture, Cancer research, Female, Research Article, medicine.drug, Endocrine resistance, Src
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.

Published
2021

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