title: Imaging DNA damage allows detection of preneoplasia in the BALB-neuT model of breast cancer.
abstract: A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice.
  
  
  METHODS
  Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging.
  
  
  RESULTS
  γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001).
  
  
  CONCLUSIONS
  DDR imaging using (111)In-anti-γH2AX-TAT identified mammary tumors significantly earlier than MR imaging. Imaging the DDR holds promise for the detection of preneoplasia and as a technique for screening cancer-prone individuals.
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Able
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Christiana
authors.initials: C
authors.lastname: Kartsonaki
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Veerle
authors.initials: V
authors.lastname: Kersemans
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: P Danny
authors.initials: PD
authors.lastname: Allen
authors.affiliation: Molecular Biotechnology Center, University of Turin, Turin, Italy; and.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: CeSI Foundation, University G. d' Annunzio, Chieti, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Knight
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Muschel
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: Smart
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Oxford University, Oxford, United Kingdom katherine.vallis@oncology.ox.ac.uk.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vallis
mesh_terms: D000818:Animals; D004249:DNA Damage; D018450:Disease Progression; D005260:Female; D007091:Image Processing, Computer-Assisted; D018796:Immunoconjugates / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011230:Precancerous Conditions / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D018796:Immunoconjugates; D019275:Radiopharmaceuticals
keywords: BALB-NeuT; breast cancer; early diagnosis; molecular imaging; γH2AX