title: Sustained NRF2 activation in hereditary leiomyomatosis and renal cell cancer (HLRCC) and in hereditary tyrosinemia type 1 (HT1).
abstract: The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes' studies may shed light on to the roles of NRF2 activation in sporadic tumours.
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A.
authors.forename: Ivraj Singh
authors.initials: IS
authors.lastname: Sandhu
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A.
authors.forename: Nicholas James
authors.initials: NJ
authors.lastname: Maksim
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A.
authors.forename: Eva Alice
authors.initials: EA
authors.lastname: Amouzougan
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A.
authors.forename: Bryce Wilson
authors.initials: BW
authors.lastname: Gallion
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A.
authors.forename: Anthony L J
authors.initials: AL
authors.lastname: Raviele
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A. ooi@pharmacy.arizona.edu.
authors.forename: Aikseng
authors.initials: A
authors.lastname: Ooi
mesh_terms: D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D018231:Leiomyomatosis / Q000235:genetics*; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary; D012878:Skin Neoplasms / Q000235:genetics*; D020176:Tyrosinemias / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human
keywords: Kelch-like ECH-associated protein 1 (KEAP1); fumarate hydratase (FH); fumarylacetoacetate hydrolase gene (FAH); hereditary leiomyomatosis and renal cell cancer (HLRCC); hereditary tyrosinemia type 1; nuclear erythroid 2-like 2 transcription factor (NRF2)