Pharm Sci. 2023;29(1): 1-19.
doi: 10.34172/PS.2022.23

Scopus ID: 85154021829
  Abstract View: 616
  PDF Download: 432

Review Article

Modulation of Nrf2 by Activation of Estrogen Receptor β as a Therapeutic Strategy to Prevent Cancer Development and Overcome Inflammation-Related Drug Resistance in Breast Cancer

Emdormi Rymbai 1 ORCID logo, Deepa Sugumar 1, Jubie Selvaraj 2, Ram Kothandam 3, Divakar Selvaraj 1* ORCID logo

1 Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
2 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
3 Department of Biotechnology, Kumaraguru College of Technology, Coimbatore, Tamil Nadu, India.
*Corresponding Author: Email: divakar.s@jssuni.edu.in


Despite the tremendous progress in breast cancer diagnosis and treatment, the mortality rate is expected to increase due to the emergence of drug resistance. Pro-inflammatory markers are thought to contribute to drug resistance by activation of its naive receptors and its downstream signaling pathways. Elevation of pro-inflammatory markers leads to an increase in the biosynthesis of estrogen which can promote the proliferation of estrogen receptor (ER)+ breast cancer. Inflammation also results in obesity which is one of the key risk factors. Estrogen receptor-beta (ER-β) is an important target that has been widely studied and accepted to possess anti-cancer activity in a number of cancers including breast cancer. ER-β elicits its action through genomic and non-genomic pathways. The genomic pathway increases the transcription of potent cyclin-dependent kinase inhibitor (p21), and tumor suppressor genes such as melanoma differentiation associated gene 7 and tumor protein (p53). The non-genomic pathway works through protein-protein interaction and phosphorylation. Here, we propose that the activation of ER-β might enhance the activation of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) via estrogen receptor-alpha (ER-α) repression. The activation of Nrf2 increases the transcription of antioxidant genes such as NADH quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), etc., and decreases the expression of pro-inflammatory genes such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), etc. This review hypothesizes and suggests that ER-β agonists could play a beneficial role to overcome inflammation-related drug resistance by modulation of the Nrf2/antioxidant response element (Nrf2/ARE) pathway.
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Submitted: 13 Feb 2022
Revision: 05 May 2022
Accepted: 05 May 2022
ePublished: 11 May 2022
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