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01-11-2018 | Preclinical study

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

Authors: Juo-Han Lin, Shih-Hsin Tu, Li-Ching Chen, Chi-Cheng Huang, Hang-Lung Chang, Tzu-Chun Cheng, Hui-Wen Chang, Chih-Hsiung Wu, Han-Chung Wu, Yuan-Soon Ho

Published in: Breast Cancer Research and Treatment | Issue 1/2018

Abstract

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 (H₂O₂)-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 H₂O₂, with significantly inhibited proliferation and colony formation abilities. Tamoxifen-resistant (Tam-R) cells lacking GSTM3 showed enhanced sensitivity to H₂O₂, 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.

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Pink JJ, Jordan VC (1996) Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res 56:2321–2330PubMed

Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O et al (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758. https://doi.org/10.1038/39645 CrossRefPubMed

Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 7:497–508CrossRef

Zhu BT, Conney AH (1998) Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 19:1–27CrossRef

Feigelson HS, Henderson BE (1996) Estrogens and breast cancer. Carcinogenesis 17:2279–2284CrossRef

Strange RC, Spiteri MA, Ramachandran S, Fryer AA (2001) Glutathione-S-transferase family of enzymes. Mutat Res 482:21–26CrossRef

Chasseaud LF (1979) The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res 29:175–274CrossRef

Shea TC, Claflin G, Comstock KE, Sanderson BJ, Burstein NA, Keenan EJ et al (1990) Glutathione transferase activity and isoenzyme composition in primary human breast cancers. Cancer Res 50:6848–6853PubMed

Xu S, Wang Y, Roe B, Pearson WR (1998) Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion. J Biol Chem 273:3517–3527CrossRef

10.

Inskip A, Elexperu-Camiruaga J, Buxton N, Dias PS, MacIntosh J, Campbell D et al (1995) Identification of polymorphism at the glutathione S-transferase, GSTM3 locus: evidence for linkage with GSTM1*A. Biochem J 312(Pt 3):713–716CrossRef

11.

Jourenkova-Mironova N, Voho A, Bouchardy C, Wikman H, Dayer P, Benhamou S et al (1999) Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers. Int J Cancer 81:44–48CrossRef

12.

Yengi L, Inskip A, Gilford J, Alldersea J, Bailey L, Smith A et al (1996) Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma. Cancer Res 56:1974–1977PubMed

13.

Jain M, Kumar S, Lal P, Tiwari A, Ghoshal UC, Mittal B (2007) Role of GSTM3 polymorphism in the risk of developing esophageal cancer. Cancer Epidemiol Biomark Prev 16:178–181. https://doi.org/10.1158/1055-9965.EPI-06-0542 CrossRef

14.

Peng DF, Razvi M, Chen H, Washington K, Roessner A, Schneider-Stock R et al (2009) DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett’s adenocarcinoma. Gut 58:5–15. https://doi.org/10.1136/gut.2007.146290 CrossRefPubMed

15.

Sikdar N, Paul RR, Roy B (2004) Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers. Int J Cancer 109:95–101. https://doi.org/10.1002/ijc.11610 CrossRefPubMed

16.

Marques CF, Koifman S, Koifman RJ, Boffetta P, Brennan P, Hatagima A (2006) Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro. Oral Oncol 42:632–637. https://doi.org/10.1016/j.oraloncology.2005.11.003 CrossRefPubMed

17.

Yu KD, Fan L, Di GH, Yuan WT, Zheng Y, Huang W et al (2010) Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1. Breast Cancer Res Treat 121:485–496. https://doi.org/10.1007/s10549-009-0585-9 CrossRefPubMed

18.

Huerta S, Harris DM, Jazirehi A, Bonavida B, Elashoff D, Livingston EH et al (2003) Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis. Int J Oncol 22:663–670PubMed

19.

Monge M, Vilaseca M, Soto-Cerrato V, Montaner B, Giralt E, Perez-Tomas R (2007) Proteomic analysis of prodigiosin-induced apoptosis in a breast cancer mitoxantrone-resistant (MCF-7 MR) cell line. Invest New Drugs 25:21–29. https://doi.org/10.1007/s10637-006-7774-8 CrossRefPubMed

20.

Bieche I, Girault I, Urbain E, Tozlu S, Lidereau R (2004) Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma. Breast Cancer Res 6:R252–R263. https://doi.org/10.1186/bcr784 CrossRefPubMedPubMedCentral

21.

Lee CH, Chang YC, Chen CS, Tu SH, Wang YJ, Chen LC et al (2011) Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha 9-nicotinic acetylcholine receptor expression in human breast cancer cells. Breast Cancer Res Treat 129:331–345. https://doi.org/10.1007/s10549-010-1209-0 CrossRefPubMed

22.

Cheng TC, Tu SH, Chen LC, Chen MY, Chen WY, Lin YK et al (2015) Down-regulation of alpha-L-fucosidase 1 expression confers inferior survival for triple-negative breast cancer patients by modulating the glycosylation status of the tumor cell surface. Oncotarget 6:21283–21300. https://doi.org/10.18632/oncotarget.4238 CrossRefPubMedPubMedCentral

23.

Fan P, Wang J, Santen RJ, Yue W (2007) Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 67:1352–1360. https://doi.org/10.1158/0008-5472.CAN-06-1020 CrossRefPubMed

24.

Lowry NC, Pardon LP, Yates MA, Juraska JM (2010) Effects of long-term treatment with 17 beta-estradiol and medroxyprogesterone acetate on water maze performance in middle aged female rats. Horm Behav 58:200–207. https://doi.org/10.1016/j.yhbeh.2010.03.018 CrossRefPubMedPubMedCentral

25.

Gordon MN, Osterburg HH, May PC, Finch CE (1986) Effective oral administration of 17 beta-estradiol to female C57BL/6J mice through the drinking water. Biol Reprod 35:1088–1095CrossRef

26.

Kang JS, Kang MR, Han SB, Yoon WK, Kim JH, Lee TC et al (2009) Low dose estrogen supplementation reduces mortality of mice in estrogen-dependent human tumor xenograft model. Biol Pharm Bull 32:150–152CrossRef

27.

Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282. https://doi.org/10.1056/NEJMra050776 CrossRefPubMed

28.

Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM et al (2000) Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 74:311–317CrossRef

29.

Welboren WJ, Stunnenberg HG, Sweep FC, Span PN (2007) Identifying estrogen receptor target genes. Mol Oncol 1:138–143. https://doi.org/10.1016/j.molonc.2007.04.001 CrossRefPubMedPubMedCentral

30.

Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19:833–842. https://doi.org/10.1210/me.2004-0486 CrossRefPubMed

31.

O’Lone R, Frith MC, Karlsson EK, Hansen U (2004) Genomic targets of nuclear estrogen receptors. Mol Endocrinol 18:1859–1875. https://doi.org/10.1210/me.2003-0044 CrossRefPubMed

32.

McIlwain CC, Townsend DM, Tew KD (2006) Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene 25:1639–1648. https://doi.org/10.1038/sj.onc.1209373 CrossRefPubMed

33.

Watson MB, Lind MJ, Smith L, Drew PJ, Cawkwell L (2007) Expression microarray analysis reveals genes associated with in vitro resistance to cisplatin in a cell line model. Acta Oncol 46:651–658. https://doi.org/10.1080/02841860601156157 CrossRefPubMed

34.

Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247. https://doi.org/10.1146/annurev-med-070909-182917 CrossRefPubMedPubMedCentral

35.

Yang GP, Ross DT, Kuang WW, Brown PO, Weigel RJ (1999) Combining SSH and cDNA microarrays for rapid identification of differentially expressed genes. Nucleic Acids Res 27:1517–1523CrossRef

36.

Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J, Cervera N et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25:2273–2284. https://doi.org/10.1038/sj.onc.1209254 CrossRefPubMed

37.

Anttila S, Luostarinen L, Hirvonen A, Elovaara E, Karjalainen A, Nurminen T et al (1995) Pulmonary expression of glutathione S-transferase M3 in lung cancer patients: association with GSTM1 polymorphism, smoking, and asbestos exposure. Cancer Res 55:3305–3309PubMed

38.

Kesarwani P, Singh R, Mittal RD (2009) Association of GSTM3 intron 6 variant with cigarette smoking, tobacco chewing and alcohol as modifier factors for prostate cancer risk. Arch Toxicol 83:351–356. https://doi.org/10.1007/s00204-008-0343-5 CrossRefPubMed

39.

Li YS, Liu M, Nakata Y, Tang HB (2011) beta-catenin accumulation in nuclei of hepatocellular carcinoma cells up-regulates glutathione-s-transferase M3 mRNA. World J Gastroenterol 17:1772–1778. https://doi.org/10.3748/wjg.v17.i13.1772 CrossRefPubMedPubMedCentral

40.

Felty Q, Singh KP, Roy D (2005) Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 24:4883–4893. https://doi.org/10.1038/sj.onc.1208667 CrossRefPubMed

41.

Patel MM, Bhat HK (2004) Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: involvement of metabolic activation and cytochrome P450. J Biochem Mol Toxicol 18:37–42. https://doi.org/10.1002/jbt.20005 CrossRefPubMed

42.

Roy D, Cai Q, Felty Q, Narayan S (2007) Estrogen-induced generation of reactive oxygen and nitrogen species, gene damage, and estrogen-dependent cancers. J Toxicol Environ Health B Crit Rev 10:235–257. https://doi.org/10.1080/15287390600974924 CrossRefPubMed

43.

Mense SM, Remotti F, Bhan A, Singh B, El-Tamer M, Hei TK et al (2008) Estrogen-induced breast cancer: alterations in breast morphology and oxidative stress as a function of estrogen exposure. Toxicol Appl Pharmacol 232:78–85. https://doi.org/10.1016/j.taap.2008.06.007 CrossRefPubMedPubMedCentral

44.

Mitrunen K, Hirvonen A (2003) Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat Res 544:9–41CrossRef

45.

Montano MM, Deng H, Liu M, Sun X, Singal R (2004) Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23:2442–2453. https://doi.org/10.1038/sj.onc.1207358 CrossRefPubMed

46.

Prat A, Baselga J (2008) The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nat Clin Pract Oncol 5:531–542. https://doi.org/10.1038/ncponc1179 CrossRefPubMed

47.

Olopade OI, Grushko TA, Nanda R, Huo D (2008) Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res 14:7988–7999. https://doi.org/10.1158/1078-0432.CCR-08-1211 CrossRefPubMedPubMedCentral

48.

Razandi M, Pedram A, Jordan VC, Fuqua S, Levin ER (2013) Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer. Oncogene 32:3274–3285. https://doi.org/10.1038/onc.2012.335 CrossRefPubMed

49.

Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MG et al (2016) Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 6:21164. https://doi.org/10.1038/srep21164 CrossRefPubMedPubMedCentral

Title: Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity, which confers tamoxifen resistance on breast cancer cells
Authors: Juo-Han Lin
Shih-Hsin Tu
Li-Ching Chen
Chi-Cheng Huang
Hang-Lung Chang
Tzu-Chun Cheng
Hui-Wen Chang
Chih-Hsiung Wu
Han-Chung Wu
Yuan-Soon Ho
Publication date: 01-11-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4897-5

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