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Imaging DNA damage allows detection of preneoplasia in the BALB-neuT model of breast cancer

Lookup NU author(s): Dr James Knight

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Abstract

Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc. 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 111In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether 111In-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. 111In-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 111In-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 111In-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). Conclusion: DDR imaging using 111In-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.


Publication metadata

Author(s): Cornelissen B, Able S, Kartsonaki C, Kersemans V, Allen PD, Cavallo F, Cazier J-B, Iezzi M, Knight J, Muschel R, Smart S, Vallis KA

Publication type: Article

Publication status: Published

Journal: Journal of Nuclear Medicine

Year: 2014

Volume: 55

Issue: 12

Pages: 2026-2031

Print publication date: 01/12/2014

Online publication date: 13/11/2014

Acceptance date: 01/01/1900

ISSN (print): 0161-5505

ISSN (electronic): 2159-662X

Publisher: Society of Nuclear Medicine Inc.

URL: https://doi.org/10.2967/jnumed.114.142083

DOI: 10.2967/jnumed.114.142083

PubMed id: 25453049


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