title: Nrf2, the master redox switch: the Achilles' heel of ovarian cancer?
abstract: Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1-CUL3-RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Monique G P
authors.initials: MG
authors.lastname: van der Wijst
authors.affiliation: Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address: m.g.rots@umcg.nl.
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Rots
mesh_terms: D000818:Animals; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000235:genetics; D018384:Oxidative Stress
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human
keywords: Cancer therapy; Mutations; Nrf2; Ovarian cancer; Oxidative stress; Reactive oxygen species