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Proc Natl Acad Sci U S A. 2014 May 27;111(21):7789-94. doi: 10.1073/pnas.1403813111. Epub 2014 May 12.

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

Author information

1
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3; and.
2
Departments of Cellular and Physiological Sciences and.
3
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.

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.

KEYWORDS:

3D clonogenic assay; human epithelial stem and progenitor cells; mammary differentiation; peroxiredoxin; superoxide dismutase

PMID:
24821780
PMCID:
PMC4040592
DOI:
10.1073/pnas.1403813111
[Indexed for MEDLINE]
Free PMC Article

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