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

Venugopal R Bovilla^1,2,3, Mahadevaswamy G Kuruburu^1,2, Vidya G Bettada^1,2

¹Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India.

|September 28, 2021

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.

Insights

Nuclear factor erythroid-2 related factor-2 (Nrf2) drives breast cancer progression and chemoresistance. Inhibiting Nrf2 in breast cancer cells and mouse models reduced tumor growth and sensitized cells to chemotherapy, suggesting therapeutic potential.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Nuclear factor erythroid-2 related factor-2 (Nrf2) is a key regulator of oxidative stress response.
Nrf2's role in breast cancer (BC) progression and chemotherapy response is not fully understood.
Nrf2 activation is implicated in metabolic reprogramming, inflammation, and therapeutic resistance in cancer.

Purpose of the Study:

To investigate Nrf2 expression in breast cancer tissues and cell lines.
To determine the effect of Nrf2 inhibition on breast cancer cell behavior and chemosensitivity.
To evaluate the therapeutic potential of Nrf2 inhibition in preclinical breast cancer models.

Main Methods:

Immunohistochemical analysis of Nrf2 expression in breast cancer tissues and cell lines.
Pharmacological inhibition and siRNA-mediated knockdown of Nrf2.
Assessment of cell proliferation, migration, cell cycle, apoptosis, and chemosensitivity (cisplatin) in vitro.
In vivo studies using Ehrlich Ascites Carcinoma (EAC) cells and Nrf2 inhibitor brusatol in mouse models.

Main Results:

Nrf2 expression was observed in breast cancer tissues and cell lines.
Inhibition of Nrf2 decreased NADPH quinone oxidoreductase 1 (NQO1) activity, reduced BC cell proliferation and migration, induced cell cycle arrest and apoptosis.
Nrf2 inhibition sensitized breast cancer cells to cisplatin treatment in vitro.
In vivo administration of brusatol slowed tumor growth and increased lymphocyte trafficking to the tumor microenvironment.

Conclusions:

Nrf2 signaling plays a significant role in breast cancer progression and chemoresistance.
Targeting Nrf2 with inhibitors like brusatol demonstrates potential for breast cancer therapy.
Further large-scale studies are warranted to validate Nrf2 as a biomarker and therapeutic target for chemo-sensitization in advanced and drug-resistant breast tumors.

Read full analysis

Keywords:

Ehrlich Ascites Carcinoma cells Nrf2 breast cancer brusatol chemo sensitization tumorigenesis

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