Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity, which confers tamoxifen resistance on breast cancer cells

• Published in: Breast cancer research and treatment Vol. 172; no. 1; pp. 45 - 59
• Main Authors: Lin, Juo-Han, Tu, Shih-Hsin, Chen, Li-Ching, Huang, Chi-Cheng, Chang, Hang-Lung, Cheng, Tzu-Chun, Chang, Hui-Wen, Wu, Chih-Hsiung, Wu, Han-Chung, Ho, Yuan-Soon
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2018; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer cells; Cancer prevention; Cancer research; Cell proliferation; Cell Proliferation - drug effects; Chromatin; Cytotoxicity; Detoxification; Drug Resistance, Neoplasm - genetics; ErbB-2 protein; Estrogen Receptor alpha - genetics; Estrogens; Estrogens - genetics; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genes; Glutathione; Glutathione transferase; Glutathione Transferase - genetics; GSTM3 gene; Humans; Hydrogen peroxide; Hydrogen Peroxide - toxicity; Immunoprecipitation; MCF-7 Cells; Medical schools; Medicine; Medicine & Public Health; Mice; Oncology; Patients; Polymerase chain reaction; Preclinical Study; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - genetics; RNA; Signal Transduction - drug effects; siRNA; Sp1 protein; Surgery; Tamoxifen; Tamoxifen - pharmacology; Transcription factors; Tumors; Xenograft Model Antitumor Assays; Xenografts; Glutathione S-transferase mu 3; Breast cancer; Hydrogen peroxide; Tamoxifen resistance; Oestrogen receptor
• ISSN: 0167-6806; 1573-7217; 1573-7217
• DOI: 10.1007/s10549-018-4897-5

Purpose Glutathione S-transferase mu 3 (GSTM3) is an enzyme involving in the detoxification of electrophilic compounds by conjugation with glutathione. Higher GSTM3 mRNA levels were reported in patients with ERα-positive breast cancer who received only tamoxifen therapy after surgery. Thus, this study aimed to clarify the oncogenic characteristics of GSTM3 in breast cancer and the mechanism of tamoxifen resistance. Methods GSTM3 expression in human breast tumour tissues ( n  = 227) was analysed by RT-PCR and quantitative PCR. Western blot, promoter activity assays, and chromatin immunoprecipitation (ChIP) assays were used to investigate the mechanism of GSTM3 gene regulation. Hydrogen peroxide (H 2 O 2 )-induced cytotoxicity in breast cancer cells was detected by MTT assays and flow cytometry. The oncogenic characteristics of GSTM3 in MCF-7 cells were examined by siRNA knockdown in soft agar assays and a xenograft animal model. Results GSTM3 mRNA was highly expressed in ER- and HER2-positive breast cancers. Moreover, patients who received adjuvant Herceptin had increased GSTM3 mRNA levels in tumour tissue. Oestrogen-activated GSTM3 gene expression through ERα-mediated recruitment of SP1, EP300, and AP-1 complexes. GSTM3-silenced MCF-7 cells were more sensitive to H 2 O 2 , with significantly inhibited proliferation and colony formation abilities. Tamoxifen-resistant (Tam-R) cells lacking GSTM3 showed enhanced sensitivity to H 2 O 2 , but this result was contrary to that obtained after short-term tamoxifen exposure. The animal model suggested that GSTM3 silencing might suppress the tumourigenic ability of MCF-7 cells and increase tumour cell apoptosis. Conclusions ROS production is one mechanism by which cancer drugs kill tumour cells, and according to our evidence, GSTM3 may play an important role in preventing breast cancer treatment-induced cellular cytotoxicity.