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ATM is required for SOD2 expression and homeostasis within the mammary gland

Lisa M Dyer1,2, Jessica D Kepple1, Lingbao Ai1

  • 1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, 1600 SW Archer Road, Box 1000245, Gainesville, FL, 32610, USA.

Breast Cancer Research and Treatment
|August 30, 2017
PubMed
Abstract

Insights

ATM is crucial for mammary gland health by regulating SOD2 antioxidant expression. Deleting ATM or SOD2 impairs lactation and mammary gland structure, highlighting their vital roles.

Area of Science:

  • Cellular stress response pathways
  • Mammalian reproductive biology
  • Gene regulation in development

Background:

  • ATM (Ataxia-telangiectasia mutated) is a key kinase activated by DNA damage and oxidative stress, regulating cellular responses.
  • The NF-κB pathway is a central mediator of inflammatory and stress responses, controlling the expression of numerous target genes.
  • Superoxide dismutase 2 (SOD2), also known as MnSOD, is a critical mitochondrial antioxidant enzyme essential for protecting cells from reactive oxygen species.

Purpose of the Study:

  • To investigate whether the antioxidant enzyme SOD2 is an ATM-dependent target gene in mammary epithelial cells.
  • To determine the role of ATM and SOD2 in mammary gland development and function.
  • To characterize the phenotypes resulting from the deletion of ATM and SOD2 in the mammary gland.

Main Methods:

  • RNA interference (RNAi) was used to knockdown ATM and RelA (an NF-κB subunit) in human mammary epithelial cells and MCF10A cells.
  • Conditional knockout mouse models were generated by crossing mice with floxed Atm or Sod2 alleles with Cre recombinase under the whey acidic protein promoter.
  • Quantitative PCR (qPCR) assessed gene expression, and histological analysis examined mammary gland structure.

Main Results:

  • SOD2 expression was found to be dependent on both ATM and RelA. ATM knockdown sensitized cells to pro-oxidant conditions, with partial rescue by SOD mimetics.
  • Conditional deletion of ATM in mammary glands significantly reduced Sod2 expression.
  • Atm-deficient mice exhibited impaired mammary gland development, progressive lactation defects, abnormal lobulo-alveolar structure, reduced milk protein gene expression, and increased apoptosis, mirroring phenotypes of Sod2-deficient mammary glands.

Conclusions:

  • ATM is essential for inducing SOD2 expression in the mammary epithelium.
  • Both ATM and SOD2 play critical roles in maintaining mammary gland homeostasis and function.
  • Dysregulation of SOD2 contributes to the lactation defects observed in ATM-deficient mammary glands.
Keywords:
AntioxidantsLactationOxidative stressStress response

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