Glutathione transferase and mammary tumors

Keywords: glutathione, polymorphism, breast, cancer


The analysis of publications from the last 5 years is presented in this review.  These articles describe the relationship of glutathione transferase (GST) with mammary tumors. Most of these works are dedicated to investigating the genotypic relationship between GST and neoplasms in human. The most common are single nucleotide polymorphism of GSTP1 Val105Ile (rs1695) and gene deletions GSTM1 and GSTT1. Several publications describe polymorphisms of GSTM3(rs4970737), GSTM4 and GSTA5. These polymorphisms (especially GSTP1 Val105Ile) are associated with the risk of mammary tumors, overall survival and relapse in patients of some ethnic groups. This is as a result of reduced enzymatic activity of GST and disturb of ability to detoxify substrates. Some studies demonstrate that single nucleotide polymorphism of GSTP1 Val105IIe is associated with a better response to chemotherapy and overall survival of patients, but no association with genotypes of GSTM1 and GSTT1. The injections of carcinogenic compounds into the tissue of mammary gland or its feeding to rats leed to decrease of GST activity and to development of tumors. The increased expression of GST in breast cancer cell lines leeds to increase of the resistance of these cells against various chemical compounds therefore the enzyme catalyzes the binding of these compounds to glutathione and this prevent their negative effects and is necessary for the formation of conjugates. Such increased expression of GST indicates on the resistance of breast cancer cell lines in particular to the action of drugs, which reduces their therapeutic effect. This is shown on cell lines BT474, MCF-7, MCF-7/ADR, MCF-7/ADR-1024, MCF-10A, MDA-MB-231, MDA-MB-468 and T47D. Chemical compounds (including antitumor drugs), that reduce the activity and/or expression of GST, can have a cytotoxic effect on these cells. Mammary tumors associated with epigenetic changes that do not change the sequence of nucleotides in GST genes. The methylation of the GSTP1 promoter decreases an expression of protein in mammary tissue and increases a risk of cancer in different ethnic groups. Compounds increase the level of expression of genes when they are able to lower the level of methylation or to affect demethylation. Polymorphisms of GST genes, their association with response to chemotherapy and overall survival of patients, expression of GST and it dependence on the action of anticancer drugs, methylation of GST promoter are associated with diagnosis, prognosis, and treatment of mammary neoplasms.


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Al-Dhabi, N.A., Srigopalram, S., Ilavenil, S., Kim, Y.O., Agastian, P., Baaru, R. et al. (2016). Proteomic analy-sis of stage-II breast cancer from formalin-fixed par-affin-embedded tissues. BioMed Research Interna-tional, 2016, 1–6. doi: 10.1155/2016/3071013.

AL-Eitan, L.N., Rababah, D.M., Alghamdi, M.A., & Khasawneh, R.H. (2019). Association of GSTM1, GSTT1 and GSTP1 polymorphisms with breast cancer among Jordanian women. OncoTargets and Therapy, 12, 7757–7765. doi: 10.2147/OTT.S207255.

Al-Harras, M.F., Houssen, M.E., Shaker, M.E., Farag, K., Farouk, O., Monir, R. et al. (2016). Polymorphisms of glutathione S-transferase 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility. Oncology Letters, 11(3), 2182–2188. doi: 10.3892/ol.2016.4159.

Balamurugan, M., Sivakumar, K., Anand, M.A.V., & Suresh, K. (2017). Modulating effect of hypnea mus-ciformis (red seaweed) on lipid peroxidation, antioxi-dants and biotransforming enzymes in 7,12-dimethylbenz (a) anthracene. induced mammary car-cinogenesis in experimental animals. Pharmacognosy Research, 9(1), 108–115. doi: 10.4103/0974-8490.187085.

Balkwill, R., Mowshowitz, S., Seilman S.S., Moodie, E.M., Griffin, D.B., Fantes, K.H. et al. (1984). Positive inter-actions between interferon and chemotherapy due to direct tumor action rather than effects on host drug-metabolizing enzymes. Cancer Research, 44(11), 5249–5255.

Bansal, V.K., Rajan, K., Sharma, A., Paliwal, P., Chaubal, G., & Jindal, V. (2015). Prospective case-control study to evaluate the role of glutathione S transferases (GSTT1 and GSTM1) gene deletion in breast carci-noma and its prognostic significance. Indian Journal of Surgery, 77(3), 1067–1072. doi: 10.1007/s12262-014-1152-0.

Bhat, A., Masood, A., Wani, K.A., Bhat, YA., Nissar, B., & Khan, N.S. (2017). Promoter methylation and gene polymorphism are two independent events in regula-tion of GSTP1 gene expression. Tumor Biology, 39(4), 1–11. doi: 10.1177/1010428317697563.

Booth, J., Boyland, E., & Sims, P. (1961). An enzyme from rat liver catalysing conjugations with glutathione. Biochemical Journal, 79(3), 516–524. doi: 10.1042/bj0790516.

Cen, J., Zheng, B.B., Bai, R.B., Zhang, L., Zhang, F., & Zhang, X. (2017). Triterpenoids from Aglaia abbrevi-ata exert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen spe-cies induction and P-glycoprotein inhibition. Oncotar-get, 8(41), 69465–69476. doi: 10.18632/oncotarget.17287.

Chen, G.L., Zhang, H., Sun, L.S., Jiang, Y.L., Xu, Z., Gu, H.Z., et al. (2017). Prognostic significance of GSTP1 in patients with triple negative breast cancer. Oncotarget, 8(40), 68675–68680. doi: 10.18632/oncotarget.19824.

Deepalakshmi, K., & Mirunalini, S. (2016). Efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. on 7,12- dimethylbenz(a)anthracene induced mammary car-cinogenesis in female Sprague-Dawley rats. New Hori-zons in Translational Medicine, 3(2), 73–82. doi: 10.1016/j.nhtm.2016.06.002.

Dong, X.L., Yang, Y., Zhou, Y., Bi, X.W., Zhao, N.W., Zhang, Z.P., et al. (2019). Glutathione S-transferases P1 protects breast cancer cell from adriamycin-induced cell death through promoting autophagy. Cell Death and Differentiation, 26 (10), 2086–2099. doi: 10.1038/s41418-019-0276-y.

Fang, C., Wei, X.M., Zeng, X.T., Wang, F.B., Weng, H., & Long, X.H. (2015). Aberrant GSTP1 promoter meth-ylation is associated with increased risk and advanced stage of breast cancer: a meta-analysis of 19 case-control studies. BMC Cancer, 15(920), 1–8. doi: 10.1186/s12885-015-1926-1.

Hall, S.R., Blundon, H.L., Ladda, M.A., Robertson, A.W., Martinez-Farina, C.F., & Jakeman, D.L. (2015). Ja-domycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism. Pharmacology Research & Perspectives, 3(2), e00110. doi: 10.1002/prp2.110.

Hayes, J.D., Flanagan, J.U., & Jowsey, I.R. (2005). Gluta-thione transferases. Annual Review of Pharmacology and Toxicology, 45, 51–88. doi: 10.1146/annurev.pharmtox.45.120403.095857.

IUBMB Enzyme Nomenclature

Jahn, S.C., Solayman, M.H.M., Lorenzo, R.J., Langaee, T., Stacpoole, P.W., & James, M.O. (2016). GSTZ1 expression and chloride concentrations modulate sen-sitivity of cancer cells to dichloroacetate. Biochimica et Biophysica Acta – General Subjects, 1860(6), 1202–1210. doi: 10.1016/j.bbagen.2016.01.024.

Jaramillo-Rangel, G., Ortega-Martínez, M., Cerda-Flores, R.M., & Barrera-Saldaña H.A. (2015). Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico. Genetics and Molecular Research, 14(2), 6465–6471. doi: 10.4238/2015.

Kashiwagi, S., Fukushima, W., Asano, Y., Goto, W., Takada, K., Noda, S. et al. (2017). Identification of predictive markers of the therapeutic effect of eribulin chemotherapy for locally advanced or metastatic breast cancer. BMC Cancer, 17(604), 1–10. doi: 10.1186/s12885-017-3598-5.

Kimi, L., Ghatak, S., Yadav, R.P., Chhuani, L., Lalla-wmzuali, D., Pautu, J.L. et al. (2016). Relevance of GSTM1, GSTT1 and GSTP1 gene polymorphism to breast cancer susceptibility in Mizoram population, northeast India. Biochemical Genetics, 54(1), 41–49. doi: 10.1007/s10528-015-9698-5.

Krasowska, D., Iraci, N., Santi, C., Drabowicz, J., Cieslak, M., Kazmierczak-Baranska, J. et al. (2019). Diseleni-des and benzisoselenazolones as antiproliferative agents and glutathione-S-transferase inhibitors. Mole-cules, 24(16), 1–19. doi: 10.3390/molecules24162914.

Kumar, U., Sharma, U., & Rathi, G. (2017). Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line. Tumor Biology, 39(2), 1–8. doi: 10.1177/1010428317692258.

Li, S., Lang, G.T., Zhang, Y.Z., Yu, K.D., Shao, Z.M., & Zhang, Q. (2018). Interaction between glutathione S-transferase M1-null/present polymorphism and adju-vant chemotherapy influences the survival of breast cancer. Cancer Medicine, 7(9), 4202–4207. doi: 10.1002/cam4.1567.

Li, Y.H., Jiang, B.H., Zhu, H.B., Qu, X.F., Zhao, L.Q., Tan, Y.R. et al. (2017). Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. Tumor Biology, 39(6), 1–8. doi: 10.1177/1010428317705790.

Louie, S.M., Grossman, E.A., Crawford, L.A., Ding, L., Camarda, R., Huffman, T.R. et al. (2016). GSTP1 is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chemical Biology, 23(5), 567–578. doi: 10.1016/j.chembiol.2016.03.017.

Ma, J., Zhu, S.L., Liu, Y., Huang, X.Y., & Su, D.K. (2017). GSTP1 polymorphism predicts treatment outcome and toxicities for breast cancer. Oncotarget, 8(42), 72939–72949. doi: 10.18632/oncotarget.18513.

Miao, L.F., Wang, X.Y., Ye, X.H., Cui, M.S., & He, X.F. (2019). Combined effects of GSTM1 and GSTT1 pol-ymorphisms on breast cancer risk: A MOOSE-compliant meta-analysis and false-positive report probabilities test. Medicine, 98(6), e14333. doi: 10.1097/MD.0000000000014333.

Pan, Z., Fu, Z., Song, Q., Cao, W., Cheng, W., & Xu, X. (2016). Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women. Genetics and Mo-lecular Research, 15(2), 1–9. doi: 10.4238/gmr.15028640.

Prasannakumari, J.J., Padmam, P., & Doss, V.A. (2017). Therapeutic effect of hydro-ethanolic extract of pot-hos scandens l on key carbohydrate metabolizing en-zymes and xenobiotic marker enzymes in DMBA in-duced experimental mammary carcinoma. Indian Journal of Pharmaceutical Education and Research, 51(3), 418–426. doi: 10.5530/ijper.51.3.70.

Qiu, J., Du, Z., Liu, J., Zhou, Y., Liang, F., & Lu, Q. (2018). Association between polymorphisms in estrogen me-tabolism genes and breast cancer development in Chinese women: A prospective case-control study. Medicine, 97(47), e13337. doi: 10.1097/MD.0000000000013337.

Song, Z., Shao, C., Feng, C., Lu, Y., Gao, Y., & Dong, C. (2016). Association of glutathione S-transferase T1, M1, and P1 polymorphisms in the breast cancer risk: a meta-analysis. Therapeutics and Clinical Risk Man-agement, 12, 763–769. doi: 10.2147/TCRM.S104339.

Soto-Quintana, O., Zúñiga-González, G.M., Ramírez-Patiño, R., Ramos-Silva, A., Figuera, L.E., Carrillo-Moreno, D.I. et al. (2015). Association of the GSTM1 null polymorphism with breast cancer in a Mexican population. Genetics and Molecular Research, 14, 13066–13075. doi: 10.4238/2015.

Stewart, D.A., Winnike, J.H., McRitchie, S.L., Clark, R.F., Pathmasiri, W.W., & Sumner, S.J. (2016). metabolom-ics analysis of hormone-responsive and triple-negative breast cancer cell responses to paclitaxel identify key metabolic differences. Journal of Proteome Research, 15(9), 3225–3240. doi: 10.1021/acs.jproteome.6b00430.

Szic, K.S.V., Declerck, K., Crans, R.A.J., Diddens, J., Scherf, D.B., Gerhauser, C. Epigenetic silencing of tri-ple negative breast cancer hallmarks by Withaferin A. Oncotarget, 8(25), 40434–40453. doi: 10.18632/oncotarget.17107.

Telkoparan, A.P., Tuglu, Y.B., & Shomali, M.N. (2018). Anticancer, antioxidant properties and phenolic, fla-vonoid composition of Heracleum platytaenium plant methanolic extracts. Journal of Research in Pharma-cy, 22(3), 396–404. doi: 10.12991/jrp.2018.79.

Theodossiou, T.A., Olsen, C.E., Jonsson, M., Kubin, A., Hothersall, J.S., & Berg, K. (2017). The diverse roles of glutathione-associated cell resistance against hyperi-cin photodynamic therapy. Redox Biology, 12, 191–197. doi: 10.1016/j.redox.2017.02.018.

Tsou, SH., Chen, TM., Hsiao, HT., & Chen, YH. (2015). A critical dose of doxorubicin is required to alter the gene expression profiles in MCF-7 cells acquiring mul-tidrug resistance. PLoS ONE, 10(1), e0116747. doi: 10.1371/journal.pone.0116747.

Wang, J., Wang, T., Yin, G.Y., Yang, L., Wang, Z.G., & Bu, X.B. (2015). Glutathione S-transferase polymor-phisms influence chemotherapy response and treat-ment outcome in breast cancer. Genetics and Molecu-lar Research, 14(3), 11126–11132. doi: 10.4238/2015. September.22.6.

Wang, W., Xu, Z.Z., Costanzo, M., Boone, C., Lange, C.A., & Myers, C.L. (2017). Pathway-based discovery of genetic interactions in breast cancer. PLoS Genetics, 13(9), e1006973. doi: 10.1371/journal.pgen.1006973.

Wang, X., & Huang, Z.H. (2015). Predictive potential role of glutathione S-transferase polymorphisms in the prognosis of breast cancer. Genetics and Molecular Research, 14(3), 10236–10241. doi: 10.4238/2015. August.28.7.

Wang, Z.P., Liang, S., Lian, X., Liu, L., Zhao, S., & Xuan, Q.J. (2015). Identification of proteins responsible for adriamycin resistance in breast cancer cells using pro-teomics analysis. Scientific Reports, 5(9301), 1–9. doi: 10.1038/srep09301.

Wu, L., Shen, Y., Peng, X.Z., Zhang, S.M., Wang, M., Xu, G.S. et al. (2016). Aberrant promoter methylation of cancer-related genes in human breast cancer. Oncolo-gy Letters, 12(6), 5145–5155. doi: 10.3892/ol.2016.5351.

Yager, J.D. (2015). Mechanisms of estrogen carcinogene-sis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention – A review. Steroids, 99(A), 56–60. doi: 10.1016/j.steroids.2014.08.006.

Yang, M.L., Li, Y.R., Shen, X.F., Ruan, Y., Lu, Y., & Jin, X.S. (2017). CLDN6 promotes chemoresistance through GSTP1 in human breast cancer. Journal of Experimental & Clinical Cancer Research, 36(157), 1–15. doi: 10.1186/s13046-017-0627-9.

Yuan, P., Yuan, L., Xu, B.L., Wang, C.Z., Yang, H.Z., & Li, Y. (2015). Predictive potential role of glutathione S-transferases polymorphisms in response to chemo-therapy and breast cancer prognosis. Genetics and Molecular Research, 14(4), 16675–16681. doi: 10.18632/oncotarget.18513.

Zhang, J., Wu, Y., Hu, X.C., Wang, B.Y., Wang, L.P., Zhang, S. et al. (2017). GSTT1, GSTP1, and GSTM1 genetic variants are associated with survival in previ-ously untreated metastatic breast cancer. Oncotarget, 8(62), 105905–105914. doi: 10.18632/oncotarget.22450.

Zhang, Z.Y., Lin, G.H., Yan, Y.J., Li, X., Hu, Y.B., Wang, J. et al. (2018). Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene, 37(25), 3456–3470. doi: 10.1038/s41388-018-0221-4.

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Fedets, O., & Kurlyak, I. (2019). Glutathione transferase and mammary tumors. Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies. Series: Veterinary Sciences, 21(96), 164-170.