title: Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland.
abstract: OBJECTIVE
  Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood, and adolescence confers the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multistage process of breast cancer development. In this study, we investigated the long-term pathophysiologic effects of ionizing radiation at a dose (2 Gy) relevant to fractionated radiotherapy.
  
  
  METHODS
  Adolescent (6-8 weeks old; n = 10) female C57BL/6J mice were exposed to 2 Gy total body γ-radiation, the mammary glands were surgically removed, and serum and urine samples were collected 2 and 12 months after exposure. Molecular pathways involving estrogen receptor-α (ERα) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and Western blot.
  
  
  RESULTS
  Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16αOHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated vs. control mice. Marked increase in p85α, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ERα in mammary tissues 2 and 12 months after radiation exposure was also observed.
  
  
  CONCLUSIONS
  Taken together, our data not only support epidemiologic observations associating radiation and breast cancer but also, specify molecular events that could be involved in radiation-induced breast cancer.
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057-1468, USA.
authors.forename: Shubhankar
authors.initials: S
authors.lastname: Suman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Kamal
authors.initials: K
authors.lastname: Datta
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D004958:Estradiol / Q000097:blood*; D004967:Estrogens / Q000652:urine; D005260:Female; D019394:Ki-67 Antigen / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000209:etiology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D039181:Steroid 16-alpha-Hydroxylase / Q000652:urine*; D014916:Whole-Body Irradiation
chemical_list: D004967:Estrogens; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D019938:Cyclin D1; D004958:Estradiol; D039181:Steroid 16-alpha-Hydroxylase; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt