title: Antioxidant enzymes mediate survival of breast cancer cells deprived of extracellular matrix.
abstract: Metastasis by cancer cells relies upon the acquisition of the ability to evade anoikis, a cell death process elicited by detachment from extracellular matrix (ECM). The molecular mechanisms that ECM-detached cancer cells use to survive are not understood. Striking increases in reactive oxygen species (ROS) occur in ECM-detached mammary epithelial cells, threatening cell viability by inhibiting ATP production, suggesting that ROS must be neutralized if cells are to survive ECM-detachment. Here, we report the discovery of a prominent role for antioxidant enzymes, including catalase and superoxide dismutase, in facilitating the survival of breast cancer cells after ECM-detachment. Enhanced expression of antioxidant enzymes in nonmalignant mammary epithelial cells detached from ECM resulted in ATP elevation and survival in the luminal space of mammary acini. Conversely, silencing antioxidant enzyme expression in multiple breast cancer cell lines caused ATP reduction and compromised anchorage-independent growth. Notably, antioxidant enzyme-deficient cancer cells were compromised in their ability to form tumors in mice. In aggregate, our results reveal a vital role for antioxidant enzyme activity in maintaining metabolic activity and anchorage-independent growth in breast cancer cells. Furthermore, these findings imply that eliminating antioxidant enzyme activity may be an effective strategy to enhance susceptibility to cell death in cancer cells that may otherwise survive ECM-detachment.
authors.affiliation: Department of Biological Sciences; Notre Dame Integrated Imaging Facility, and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Calli A
authors.initials: CA
authors.lastname: Davison
authors.forename: Sienna M
authors.initials: SM
authors.lastname: Durbin
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Thau
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Zellmer
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Chapman
authors.forename: Justin
authors.initials: J
authors.lastname: Diener
authors.forename: Connor
authors.initials: C
authors.lastname: Wathen
authors.forename: W Matthew
authors.initials: WM
authors.lastname: Leevy
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Schafer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays; D000099156:Superoxide Dismutase 2
chemical_list: D000255:Adenosine Triphosphate; D000975:Antioxidants; D001205:Ascorbic Acid; D002374:Catalase; D002392:Catechin; D002839:Chromans; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C045651:epigallocatechin gallate; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid