PMID- 34572304 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240404 IS - 2227-9059 (Print) IS - 2227-9059 (Electronic) IS - 2227-9059 (Linking) VI - 9 IP - 9 DP - 2021 Aug 30 TI - Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo. LID - 10.3390/biomedicines9091119 [doi] LID - 1119 AB - 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. FAU - Bovilla, Venugopal R AU - Bovilla VR AUID- ORCID: 0000-0001-7244-9817 AD - Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Public Health Research Institute of India (PHRII), Mysuru 570020, Karnataka, India. FAU - Kuruburu, Mahadevaswamy G AU - Kuruburu MG AD - Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. FAU - Bettada, Vidya G AU - Bettada VG AD - Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. FAU - Krishnamurthy, Jayashree AU - Krishnamurthy J AD - Department of Pathology, JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. FAU - Sukocheva, Olga A AU - Sukocheva OA AUID- ORCID: 0000-0003-1041-3311 AD - College of Nursing and Health Sciences, Flinders University, Bedford Park, SA 5042, Australia. FAU - Thimmulappa, Rajesh K AU - Thimmulappa RK AD - Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. FAU - Shivananju, Nanjunda Swamy AU - Shivananju NS AD - Department of Biotechnology, JSS Technical Institutions Campus, JSS Science and Technology University, Mysore 570006, Karnataka, India. FAU - Balakrishna, Janardhan P AU - Balakrishna JP AD - Department of Stem Cell Biology, Stellixer Biotech Pvt Ltd., Banglore 560058, Karnataka, India. FAU - Madhunapantula, SubbaRao V AU - Madhunapantula SV AUID- ORCID: 0000-0001-9167-9271 AD - Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center), JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. AD - Leader, Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Academy of Higher Education & Research, Mysore 570015, Karnataka, India. LA - eng GR - D43 TW010540/TW/FIC NIH HHS/United States PT - Journal Article DEP - 20210830 PL - Switzerland TA - Biomedicines JT - Biomedicines JID - 101691304 PMC - PMC8471069 OTO - NOTNLM OT - Ehrlich Ascites Carcinoma cells OT - Nrf2 OT - breast cancer OT - brusatol OT - chemo sensitization OT - tumorigenesis COIS- The authors declare no conflict of interest. EDAT- 2021/09/29 06:00 MHDA- 2021/09/29 06:01 PMCR- 2021/08/30 CRDT- 2021/09/28 01:05 PHST- 2021/07/29 00:00 [received] PHST- 2021/08/21 00:00 [revised] PHST- 2021/08/26 00:00 [accepted] PHST- 2021/09/28 01:05 [entrez] PHST- 2021/09/29 06:00 [pubmed] PHST- 2021/09/29 06:01 [medline] PHST- 2021/08/30 00:00 [pmc-release] AID - biomedicines9091119 [pii] AID - biomedicines-09-01119 [pii] AID - 10.3390/biomedicines9091119 [doi] PST - epublish SO - Biomedicines. 2021 Aug 30;9(9):1119. doi: 10.3390/biomedicines9091119.