title: Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets.
abstract: Mechanisms that control the levels and activities of reactive oxygen species (ROS) in normal human mammary cells are poorly understood. We show that purified normal human basal mammary epithelial cells maintain low levels of ROS primarily by a glutathione-dependent but inefficient antioxidant mechanism that uses mitochondrial glutathione peroxidase 2. In contrast, the matching purified luminal progenitor cells contain higher levels of ROS, multiple glutathione-independent antioxidants and oxidative nucleotide damage-controlling proteins and consume O2 at a higher rate. The luminal progenitor cells are more resistant to glutathione depletion than the basal cells, including those with in vivo and in vitro proliferation and differentiation activity. The luminal progenitors also are more resistant to H2O2 or ionizing radiation. Importantly, even freshly isolated "steady-state" normal luminal progenitors show elevated levels of unrepaired oxidative DNA damage. Distinct ROS control mechanisms operating in different subsets of normal human mammary cells could have differentiation state-specific functions and long-term consequences.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Long V
authors.initials: LV
authors.lastname: Nguyen
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Maisam
authors.initials: M
authors.lastname: Makarem
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Kingsley
authors.initials: K
authors.lastname: Shih
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Eirew
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
authors.forename: Afshin
authors.initials: A
authors.lastname: Raouf
authors.affiliation: Departments of Cellular and Physiological Sciences and.
authors.forename: Joanne T
authors.initials: JT
authors.lastname: Emerman
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; andMedical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 ceaves@bccrc.ca.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D015153:Blotting, Western; D004249:DNA Damage / Q000502:physiology; D004847:Epithelial Cells / Q000145:classification* / Q000378:metabolism*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005978:Glutathione
keywords: 3D clonogenic assay; human epithelial stem and progenitor cells; mammary differentiation; peroxiredoxin; superoxide dismutase