Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo

Abstract

Nuclear factor erythroid-2 related factor-2 (Nrf2) is an oxidative stress-response transcriptional activator that promotes carcinogenesis through metabolic reprogramming, tumor promoting inflammation, and therapeutic resistance. However, the extension of Nrf2 expression and its involvement in regulation of breast cancer (BC) responses to chemotherapy remain largely unclear. This study determined the expression of Nrf2 in BC tissues (n = 46) and cell lines (MDA-MB-453, MCF-7, MDA-MB-231, MDA-MB-468) with diverse phenotypes. Immunohistochemical (IHC)analysis indicated lower Nrf2 expression in normal breast tissues, compared to BC samples, although the difference was not found to be significant. However, pharmacological inhibition and siRNA-induced downregulation of Nrf2 were marked by decreased activity of NADPH quinone oxidoreductase 1 (NQO1), a direct target of Nrf2. Silenced or inhibited Nrf2 signaling resulted in reduced BC proliferation and migration, cell cycle arrest, activation of apoptosis, and sensitization of BC cells to cisplatin in vitro. Ehrlich Ascites Carcinoma (EAC) cells demonstrated elevated levels of Nrf2 and were further tested in experimental mouse models in vivo. Intraperitoneal administration of pharmacological Nrf2 inhibitor brusatol slowed tumor cell growth . Brusatol increased lymphocyte trafficking towards engrafted tumor tissue in vivo, suggesting activation of anti-cancer effects in tumor microenvironment. Further large-scale BC testing is needed to confirm Nrf2 marker and therapeutic capacities for chemo sensitization in drug resistant and advanced tumors.

miR-140-5p Attenuates Hypoxia-Induced Breast Cancer Progression by Targeting Nrf2/HO-1 Axis in a Keap1-Independent Mechanism

“…Further, the luciferase assay confirmed that Nrf2 is a target of miR-140-5p. Our results are in agreement with the previous findings showing increased expression of Nrf2 in BC cells [ 8 , 9 ]. These studies suggest that miR-140-5p might induce Nrf2 mRNA degradation and inhibit its translation.…”

“…Growing evidence also supports the role of Nrf2 in activating and maintaining the Hif-1α response as silencing Nrf2 reduces Hif-1α level [6,7]. In addition, a recent study showed elevated levels of Nrf2 in BC tissue and breast cancer stem cells, further confirming its cancer-promoting roles [8][9][10]. Thus, targeting Nrf2 could be a promising chemotherapeutic strategy for treating solid tumors.…”

Brusatol Inhibits Proliferation and Invasion of Glioblastoma by Down-Regulating the Expression of ECM1

“…In addition, the study by Liang et al showed that Bru possessed its protective role in a rat model of oxygen-induced retinopathy of prematurity via counteracting microglial activation and cellular angiogenesis ( Liang and Wang, 2021 ). Inversely, a study showed that Bru could exert its inhibitory effect in breast cancer by stimulating lymphocyte migration towards tumor tissues and activating anti-tumor immune responses in vivo ( Bovilla et al, 2021 ). Obviously, this discrepancy can’t be briefly explained by Bru-dependent inhibition of Nrf2 and whether the inflammation-related effects also play important role in Bru treatment still need further study.…”

Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis (Review)

“…Nrf2 pathway inhibition represents an attractive target for developing anticancer drugs ( 37 – 46 ) ( Table II ). The core results in Table II are summarized in illustrative Fig.…”

“…Nrf2 inhibitors specifically blocked the progression of Nrf2-positive cancers ( 39 ). Pharmacological inhibition and siRNA-induced downregulation of Nrf2 signaling in breast cancer cells resulted in sensitization of cancer cells to cisplatin ( 46 ). Nrf2 small-interfering RNA induces apoptosis and inhibits proliferation in various cancer cells ( 39 , 44 – 46 ).…”