Antioxidant-mediated Up-regulation of OGG1 Via NRF2 Induction is Associated with Inhibition of Oxidative DNA Damage in Estrogen-induced Breast Cancer

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2013 May 24

PMID 23697596

Citations 52

Authors

Bhupendra Singh

Anwesha Chatterjee

Amruta M Ronghe

Nimee K Bhat

Hari K Bhat

Affiliations

Soon will be listed here.

Abstract

Background: Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis.

Methods: Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2.

Results: The expression of OGG1 was suppressed in mammary tissues and in mammary tumors of rats treated with E2. Expression of NRF2 was also significantly suppressed in E2-treated mammary tissues and in mammary tumors. Vitamin C or BHA treatment prevented E2-mediated decrease in OGG1 and NRF2 levels in the mammary tissues. Chromatin immunoprecipitation analysis confirmed that antioxidant-mediated induction of OGG1 was through increased direct binding of NRF2 to the promoter region of OGG1. Studies using silencer RNA confirmed the role of OGG1 in inhibition of oxidative DNA damage.

Conclusions: Our studies suggest that antioxidants Vit C and BHA provide protection against oxidative DNA damage and E2-induced mammary carcinogenesis, at least in part, through NRF2-mediated induction of OGG1.

Citing Articles

Protective Effects of Sulforaphane Preventing Inflammation and Oxidative Stress to Enhance Metabolic Health: A Narrative Review.

Alves I, Araujo E, Dalgaard L, Singh S, Borsheim E, Carvalho E Nutrients. 2025; 17(3).

PMID: 39940284 PMC: 11821257. DOI: 10.3390/nu17030428.

Therapeutic upregulation of DNA repair pathways: strategies and small molecule activators.

Song J, Park C, Cabanting F, Jun Y RSC Med Chem. 2024; .

PMID: 39430950 PMC: 11487406. DOI: 10.1039/d4md00673a.

Exploring the Therapeutic Implications of Co-Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer.

Calheiros-Lobo M, Silva J, Pinto B, Monteiro L, Silva P, Bousbaa H Pharmaceutics. 2024; 16(9).

PMID: 39339232 PMC: 11435222. DOI: 10.3390/pharmaceutics16091196.

Oxidative Stress and Age-Related Tumors.

Di Carlo E, Sorrentino C Antioxidants (Basel). 2024; 13(9).

PMID: 39334768 PMC: 11428699. DOI: 10.3390/antiox13091109.

Nrf-2 as a novel target in radiation induced lung injury.

Chen Y, Wang M, Zuo C, Mao M, Peng X, Cai J Heliyon. 2024; 10(8):e29492.

PMID: 38665580 PMC: 11043957. DOI: 10.1016/j.heliyon.2024.e29492.

References

Mense S, Remotti F, Bhan A, Singh B, El-Tamer M, Hei T . Estrogen-induced breast cancer: alterations in breast morphology and oxidative stress as a function of estrogen exposure. Toxicol Appl Pharmacol. 2008; 232(1):78-85. PMC: 2593408. DOI: 10.1016/j.taap.2008.06.007. View

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

Dhenaut A, Boiteux S, Radicella J . Characterization of the hOGG1 promoter and its expression during the cell cycle. Mutat Res. 2000; 461(2):109-18. DOI: 10.1016/s0921-8777(00)00042-2. View

Singh B, Bhat H . Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer. Carcinogenesis. 2012; 33(12):2601-10. PMC: 3510741. DOI: 10.1093/carcin/bgs300. View

Piao M, Kim K, Choi J, Choi J, Hyun J . Silver nanoparticles down-regulate Nrf2-mediated 8-oxoguanine DNA glycosylase 1 through inactivation of extracellular regulated kinase and protein kinase B in human Chang liver cells. Toxicol Lett. 2011; 207(2):143-8. DOI: 10.1016/j.toxlet.2011.09.002. View

Han X, Liehr J . DNA single-strand breaks in kidneys of Syrian hamsters treated with steroidal estrogens: hormone-induced free radical damage preceding renal malignancy. Carcinogenesis. 1994; 15(5):997-1000. DOI: 10.1093/carcin/15.5.997. View

Aburatani H, Hippo Y, Ishida T, Takashima R, Matsuba C, Kodama T . Cloning and characterization of mammalian 8-hydroxyguanine-specific DNA glycosylase/apurinic, apyrimidinic lyase, a functional mutM homologue. Cancer Res. 1997; 57(11):2151-6. View

Singh B, Mense S, Remotti F, Liu X, Bhat H . Antioxidant butylated hydroxyanisole inhibits estrogen-induced breast carcinogenesis in female ACI rats. J Biochem Mol Toxicol. 2009; 23(3):202-11. PMC: 4094238. DOI: 10.1002/jbt.20281. View

Collins A, Harrington V, Drew J, Melvin R . Nutritional modulation of DNA repair in a human intervention study. Carcinogenesis. 2003; 24(3):511-5. DOI: 10.1093/carcin/24.3.511. View

10.

Bravard A, Vacher M, Gouget B, Coutant A, de Boisferon F, Marsin S . Redox regulation of human OGG1 activity in response to cellular oxidative stress. Mol Cell Biol. 2006; 26(20):7430-6. PMC: 1636869. DOI: 10.1128/MCB.00624-06. View

11.

Singh K, Treas J, Tyagi T, Gao W . DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells. Cancer Lett. 2011; 316(1):62-9. DOI: 10.1016/j.canlet.2011.10.022. View

12.

Singh B, Bhat N, Bhat H . Partial inhibition of estrogen-induced mammary carcinogenesis in rats by tamoxifen: balance between oxidant stress and estrogen responsiveness. PLoS One. 2011; 6(9):e25125. PMC: 3180376. DOI: 10.1371/journal.pone.0025125. View

13.

Cavalieri E, Stack D, Devanesan P, Todorovic R, Dwivedy I, Higginbotham S . Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A. 1997; 94(20):10937-42. PMC: 23537. DOI: 10.1073/pnas.94.20.10937. View

14.

Dhakshinamoorthy S, Jaiswal A . Small maf (MafG and MafK) proteins negatively regulate antioxidant response element-mediated expression and antioxidant induction of the NAD(P)H:Quinone oxidoreductase1 gene. J Biol Chem. 2000; 275(51):40134-41. DOI: 10.1074/jbc.M003531200. View

15.

Singh B, Mense S, Bhat N, Putty S, Guthiel W, Remotti F . Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats. Toxicol Appl Pharmacol. 2010; 247(2):83-90. PMC: 4006967. DOI: 10.1016/j.taap.2010.06.011. View

16.

Arnerlov C, Emdin S, Cajander S, Bengtsson N, Tavelin B, Roos G . Intratumoral variations in DNA ploidy and s-phase fraction in human breast cancer. Anal Cell Pathol. 2002; 23(1):21-8. PMC: 4618211. DOI: 10.1155/2001/430674. View

17.

Kensler T, Wakabayashi N . Nrf2: friend or foe for chemoprevention?. Carcinogenesis. 2009; 31(1):90-9. PMC: 2802668. DOI: 10.1093/carcin/bgp231. View

18.

Tudek B, Swoboda M, Kowalczyk P, Olinski R . Modulation of oxidative DNA damage repair by the diet, inflammation and neoplastic transformation. J Physiol Pharmacol. 2007; 57 Suppl 7:33-49. View

19.

Montano M, Chaplin L, Deng H, Mesia-Vela S, Gaikwad N, Zahid M . Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis. Oncogene. 2006; 26(24):3587-90. DOI: 10.1038/sj.onc.1210144. View

20.

Henderson B, Feigelson H . Hormonal carcinogenesis. Carcinogenesis. 2000; 21(3):427-33. DOI: 10.1093/carcin/21.3.427. View