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

作者：Dyer Lisa M; Kepple Jessica D; Ai Lingbao; Kim Wan Ju; Stanton Virginia L; Reinhard Mary K; Backman Lindsey R F; Streitfeld W Scott; Babu Nivetha Ramesh; Treiber Nicolai; Scharffetter Kochanek Karin; McKinnon Peter J; Brown Kevin D^*

来源：Breast Cancer Research and Treatment, 2017, 166(3): 725-741.

DOI：10.1007/s10549-017-4424-0

• Lactation
• Oxidative stress
• Antioxidants
• Stress response

ATM activates the NF-kappa B transcriptional complex in response to genotoxic and oxidative stress. The purpose of this study was to examine if the NF-kappa B target gene and critical antioxidant SOD2 (MnSOD) in cultured mammary epithelium is also ATM-dependent, and what phenotypes arise from deletion of ATM and SOD2 within the mammary gland.
SOD2 expression was studied in human mammary epithelial cells and MCF10A using RNAi to knockdown ATM or the NF-kappa B subunit RelA. To study ATM and SOD2 function in mammary glands, mouse lines containing Atm or Sod2 genes containing LoxP sites were mated with mice harboring Cre recombinase under the control of the whey acidic protein promoter. Quantitative PCR was used to measure gene expression, and mammary gland structure was studied using histology.
SOD2 expression is ATM- and RelA-dependent, ATM knockdown renders cells sensitive to pro-oxidant exposure, and SOD mimetics partially rescue this sensitivity. Mice with germline deletion of Atm fail to develop mature mammary glands, but using a conditional knockout approach, we determined that Atm deletion significantly diminished the expression of Sod2. We also observed that these mice (termed Atm(Delta/Delta)) displayed a progressive lactation defect as judged by reduced pup growth rate, aberrant lobulo-alveolar structure, diminished milk protein gene expression, and increased apoptosis within lactating glands. This phenotype appears to be linked to dysregulated Sod2 expression as mammary gland-specific deletion of Sod2 phenocopies defects observed in Atm(Delta/Delta) dams.
We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis.

• 出版日期2017-12