title: Oxidative stress, mammospheres and Nrf2-new implication for breast cancer therapy?
abstract: Mammosphere culture of breast cancer cell lines is an important approach used for enrichment of cancer stem cells (CSCs), which exhibit high tumorigenicity and chemoresistance features. Evidence shows that CSCs maintain lower ROS levels due to elevated expression of ROS-scavenging molecules and antioxidative enzymes, which favors the survival of the CSCs and their chemoresistance. The transcription factor NF-E2-related factor 2 (Nrf2) has emerged as the master regulator of cellular redox homeostasis, by up-regulating antioxidant response element (ARE)-bearing genes products. Although Nrf2 has long-term been regarded as a beneficial defense mechanism, accumulating studies have revealed the "dark side" of Nrf2. High constitutive levels of Nrf2 was observed in many types of tumors and cancer cell lines promoting their resistance to chemotherapeutics. In this study, we report a high expression of Nrf2 and its target genes in mammospheres compared to corresponding adherent cells. In MCF-7 and MDA-MB-231 mammmosphere cells, the Nrf2-mediated cellular protective response is significantly elevated which is associated with increased resistance to taxol and anchorage-independent growth. Brusatol, an inhibitor of the Nrf2 pathway, suppressed the protein level of Nrf2 and its target genes, enhanced intracellular ROS and sensitized mammospheres to taxol, and reduced the anchorage-independent growth. These results suggest that mammospheres rely on abnormal up-regulation of Nrf2 to maintain low intracellular ROS levels. Nrf2 inhibitors, such as brusatol, have the potential to be developed into novel adjuvant chemotherapeutic drug combinations in order to combat refractory tumor initiating CSCs.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona.
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Harder
authors.affiliation: Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, Arizona.
authors.forename: Pak K
authors.initials: PK
authors.lastname: Wong
authors.affiliation: Norris Comprehensive Cancer Center University of Southern California, Los Angeles, California.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Lang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona.
authors.forename: Donna D
authors.identifier: http://orcid.org/0000-0003-1468-6616
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D061745:Antioxidant Response Elements / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D017239:Paclitaxel
keywords: Nrf2; cancer stem cell; chemoresistance