Glutathione-dependent and -independent oxidative stress-control mechanisms distinguish normal human mammary epithelial cell subsets

Nagarajan Kannan, Long V. Nguyen, Maisam Makarem, Yifei Dong, Kingsley Shih, Peter Eirew, Afshin Raouf, Joanne T. Emerman, Connie J. Eaves

Research output: Contribution to journalArticle

37 Scopus citations

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 glutathi-one-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 nucleo-tide 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.

Original languageEnglish (US)
Pages (from-to)7789-7794
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number21
DOIs
StatePublished - May 27 2014

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Keywords

  • 3D clonogenic assay
  • Human epithelial stem and progenitor cells
  • Mammary differentiation
  • Peroxiredoxin
  • Superoxide dismutase

ASJC Scopus subject areas

  • General

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