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

• Main Authors: Emdormi Rymbai (Author), Deepa Sugumar (Author), Jubie Selvaraj (Author), Ram Kothandam (Author), Divakar Selvaraj (Author)
• Format: Book
• Published: Tabriz University of Medical Sciences, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2383-2886; 10.34172/PS.2022.23
• Keywords: breast cancer; drug resistance; er-α; er-β; inflammation; nrf2; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutical Sciences, Vol 29, Iss 1, Pp 1-19 (2023)

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.