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

Venugopal R Bovilla,Jayashree Krishnamurthy,Subbarao V Madhunapantula,Janardhan P Balakrishna,Mahadevaswamy G Kuruburu,Olga A Sukocheva,Vidya G Bettada,Rajesh K Thimmulappa,Nanjunda Swamy Shivananju

doi:10.3390/biomedicines9091119

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.

Highlights

Despite the therapeutic progress and introduction of various public health programs, breast cancer (BC) incidence and mortality rates continue to increase [1]
Using a preclinical animal model, the current study investigated whether grafted Ehrlich Ascites Carcinoma (EAC) cells are suitable for testing the anti-cancer efficacy of Nuclear factor erythroid-2 related factor-2 (Nrf2) inhibitors
The expression of Nrf2 was measured using immunohistochemistry (IHC) in the tumor tissues collected from grade-II (n = 14) and grade-III (n = 29) BC patients and compared with normal breast tissues (n = 3)

Summary

Introduction

Despite the therapeutic progress and introduction of various public health programs, breast cancer (BC) incidence and mortality rates continue to increase [1]. Current BC clinical interventions include a large variety of surgical procedures, chemotherapeutic agents, Biomedicines 2021, 9, 1119. Biomedicines 2021, 9, 1119 hormonal therapy, radiotherapy, and immunotherapeutic approaches [2,3,4,5]. The highly successful BC chemotherapeutic agents, including doxorubicin/epirubicin, docetaxel, and paclitaxel [6,7], target early-stage tumors. Extensive and prolonged treatment often results in the development of BC resistance [3], accompanied by systemic toxicity [13]. The benefits of advanced genetic testing and personalized medicine-based approaches for BC treatment are not yet available for the wider population, especially in developing countries [14,15,16]. Identifying multi-functional key regulatory proteins that can be effectively targeted to control malignant transformation, spreading, and therapy resistance, has become increasingly important

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