GSTT1 and GSTM1 deletion polymorphism as a predictor of response to hormonal therapy for breast cancer
- Authors: Gulian I.S.1,2, Bystritskaya E.P.3, Otstavnykh N.Y.3, Khudchenko E.V.4, Eliseeva E.V.1, Apanasevich V.I.1, Isaeva M.P.3
-
Affiliations:
- Pacific State Medical University
- Far Eastern Federal University
- Pacific Institute of Bioorganic Chemistry n.a. G.B. Elyakov, Far Eastern Branch of the Russian Academy of Sciences
- Primorsky Regional Oncology Center
- Issue: Vol 30, No 11 (2023)
- Pages: 60-64
- Section: Original articles
- URL: https://journals.eco-vector.com/2073-4034/article/view/625811
- DOI: https://doi.org/10.18565/pharmateca.2023.11.60-64
- ID: 625811
Cite item
Open Access
Access granted
Abstract
Objective. Evaluation of the effects of GSTT1 and GSTM1 deletion polymorphisms on the risk of relapse in patients with hormone-positive breast cancer (BC) treated with tamoxifen.
Methods. The study examined blood samples from 102 women diagnosed with stage IIA–III BC, aged from 23 to 79 (average age – 48±13) years, who received adjuvant hormonal therapy (HT). Identification of deletion (null) genotypes of GSTM1 and GSTT1 was carried out using multiplex polymerase chain reaction followed by analysis of melting curves of the reaction products.
Results. A statistically significant association between the double GSTT1-GSTM1 deletions carriage and a reduced risk of developing BC relapse was revealed. According to estimates, in such patients the probability of relapse was 4.5 times lower compared with carriers of the “functional” GSTT1 and GSTM1 genotypes simultaneously (OR=0.219, 95% CI: 0.033–1.444, χ²=4.377; P=0.037). At the same time, the presence of a “null” GSTT1 variant reduced the relative risk (RR) of developing BC relapse by 1.9 times (RR=0.513, 95% CI: 0.211–1.246, χ²=2.909) compared with carriage of functionally active forms of GSTT1 (0/+, +/+). In this case, we can only talk about an emerging trend, because there was no statistically significant difference in values (P=0.089). According to estimates, the RR for the development of BC recurrence in the group of patients with a functionally inactive form of GSTM1 (0/0) was 1.2 times lower (RR=0.856, 95% CI: 0.541–1.356, χ²=0.442; P=0.507), however the resulting difference was not statistically significant.
Conclusion. A study of deletion polymorphisms of glutathione-S-transferase genes in women with BC revealed a significant association of the combination of “null” genotypes GSTM1 and GSTT1 with a reduced risk of disease relapse. Thus, carriage of these genotypes, leading to the absence of the corresponding glutathione-S-transferases, can be considered as a favorable predictive factor when conducting adjuvant HT with tamoxifen in patients with luminal BC type.
Full Text
About the authors
I. S. Gulian
Pacific State Medical University; Far Eastern Federal University
Author for correspondence.
Email: isabella.g@mail.ru
ORCID iD: 0000-0001-7072-1688
Teaching Assistant at the Institute of Surgery, Pacific State Medical University; Oncologist, Medical Center, Far Eastern Federal University
Russian Federation, Vladivostok; VladivostokE. P. Bystritskaya
Pacific Institute of Bioorganic Chemistry n.a. G.B. Elyakov, Far Eastern Branch of the Russian Academy of Sciences
Email: isabella.g@mail.ru
ORCID iD: 0000-0002-6656-6299
Russian Federation, Vladivostok
N. Yu. Otstavnykh
Pacific Institute of Bioorganic Chemistry n.a. G.B. Elyakov, Far Eastern Branch of the Russian Academy of Sciences
Email: isabella.g@mail.ru
ORCID iD: 0000-0002-0993-1763
Russian Federation, Vladivostok
E. V. Khudchenko
Primorsky Regional Oncology Center
Email: isabella.g@mail.ru
ORCID iD: 0009-0005-8426-981X
Russian Federation, Vladivostok
E. V. Eliseeva
Pacific State Medical University
Email: isabella.g@mail.ru
ORCID iD: 0000-0001-6126-1253
Russian Federation, Vladivostok
V. I. Apanasevich
Pacific State Medical University
Email: isabella.g@mail.ru
ORCID iD: 0000-0003-0808-5283
Russian Federation, Vladivostok
M. P. Isaeva
Pacific Institute of Bioorganic Chemistry n.a. G.B. Elyakov, Far Eastern Branch of the Russian Academy of Sciences
Email: isabella.g@mail.ru
ORCID iD: 0000-0002-2395-0485
Russian Federation, Vladivostok
References
- Peleg Hasson S., Brezis M.R., Shachar E., et al. Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis. ESMO. Open. 2021;6(2):100088. doi: 10.1016/j.esmoop.2021.100088.
- Bhardwaj P., Au C.C., Benito-Martin A., et al. Estrogens and breast cancer: Mechanisms involved in obesity-related development, growth and progression. J Steroid Biochem Mol Biol. 2019;189:161–70. doi: 10.1016/j.jsbmb.2019.03.002.
- Assender J.W., Gee J.M., Lewis I., et al. Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer. J Clin Pathol. 2007;60(11):1216–21. doi: 10.1136/jcp.2006.041616.
- Yao J., Deng K., Huang J., et al. Progress in the Understanding of the Mechanism of Tamoxifen Resistance in Breast Cancer. Front Pharmacol. 2020;11:592912. doi: 10.3389/fphar.2020.592912.
- Hayes J.D., Flanagan J.U., Jowsey I.R. Glutathione transferases. Ann Rev Pharmacol Toxicol. 2005;45:51–88.
- Singh S. Cytoprotective and regulatory functions of glutathione S-transferases in cancer cell proliferation and cell death. Cancer Chemother Pharmacol. 2015;75(1):1–15. doi: 10.1007/s00280-014-2566-x.
- Allocati N., Masulli M., Di Ilio C., Federici L. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis. 2018;7(1):8. doi: 10.1038/s41389-017-0025-3.
- Megias-Vericat J.E., Martinez-Cuadron D., Herrero M.J., et al. Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia. Curr Drug Metab. 2018;19(1):55–74. doi: 10.2174/1389200218666171101124931.
- Hollman A.L., Tchounwou P.B., Huang H.C. The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants. Int J Environ Res Public Health. 2016;13(4):379. doi: 10.3390/ijerph13040379.
- Medeiros R., Pereira D., Afonso N., et al. Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome. Int J Clin Oncol. 2003;8(3):156–61. doi: 10.1007/s10147-003-0318-8.
- Lourenco G.J., Lorand-Metze I., Delamain M.T., et al. Polymorphisms of glutathione S-transferase mu 1, theta 1, and pi 1 genes and prognosis in Hodgkin lymphoma. Leuk Lymphoma. 2010;51(12):2215–21. doi: 10.3109/10428194.2010.527402.
- Pereira D., Assis J., Gomes M., et al. Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile. Eur J Clin Pharmacol. 2016;72:545–53. doi: 10.1007/s00228-016-2015-3.
- Pacholak L.M., Amarante M.K., Guembarovski R.L., et al. Polymorphisms in GSTT1 and GSTM1 genes as possible risk factors for susceptibility to breast cancer development and their influence in chemotherapy response: a systematic review. Mol Biol Rep. 2020;47:5495–501. doi: 10.1007/s11033-020-05555-8.
- Гулян И.С., Быстрицкая Е.П., Чернышева Н.Ю. и др. Делеционный полиморфизм генов глутатион-S-трансфераз (GSTT1, GSTM1) у пациенток с раком молочной железы в Приморском крае. Опухоли женской репродуктивной системы. 2020;16(3):25–31. [Gulyan I.S., Bystritskaya E.P., Chernysheva N.Yu., et al. Deletion polymorphism of glutathione S-transferases genes (GSTT1, GSTM1) in patients with breast cancer in Primorye region. Tumors Female Reprod Syst. 2020;16(3):25–31. (In Russ.)]. doi: 10.17650/1994-4098-2020-16-3-25-31.
- Coles B.F., Kadlubar F.F. Detoxification of electrophilic compounds by glutathione S-transferase catalysis: determinants of individual response to chemical carcinogens and chemotherapeutic drugs? Biofactors. 2003;17(1–4):115–30. doi: 10.1002/biof.5520170112.
- Yang G., Shu X.O., Ruan Z.X., et al. Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma. Cancer. 2005;103(1):52–8. doi: 10.1002/cncr.20729.
- Lin J.H., Tu S.H., Chen L.C., et al. Oestrogen receptor-regulated glutathione S-transferase mu 3 expression attenuates hydrogen peroxide-induced cytotoxicity, which confers tamoxifen resistance on breast cancer cells. Breast Cancer Res. Treat. 2018;172(1):45–59. doi: 10.1007/s10549-018-4897-5.
- Середа Е.Е., Кондакова И.В., Слонимская Е.М. Ферменты метаболизма эстрогенов и рецепторы как факторы риска развития и прогноза при раке молочной железы. Сибирский онкологический журнал. 2004;1(9):35–43. [Sereda E.E., Kondakova I.V., Slonimskaya E.M. Estrogen metabolism enzymes and receptors as risk factors for the development and prognosis of breast cancer. Siber. J. Oncol. 2004;1(9):35–43. (In Russ.)].
- Perumal S., Shanthi P., Sachdanandam P. Augmented efcacy of tamoxifen in rat breast tumorigenesis when gavaged along with ribofavin, niacin, and CoQ10: efects on lipid peroxidation and antioxidants in mitochondria. Chem Biol Interact. 2005;152:49–58. Doi: org/10.1016/j.cbi.2005.01.007.
- Ahmed N.S., Samec M., Liskova A., et al. Tamoxifen and oxidative stress: an overlooked connection. Discov Oncol. 2021;12(1):17. doi: 10.1007/s12672-021-00411-y.
Supplementary files
