Targeting lysyl oxidase for molecular imaging in breast cancer


Targeting lysyl oxidase for molecular imaging in breast cancer

Wuest, M.; Kuchar, M.; Sharma, S. K.; Richter, S.; Wankg, M.; Vos, L.; Mackey, J. R.; Wuest, F.; Löser, R.

Objectives: Lysyl oxidase (LOX, EC 1.4.3.13) and its family members LOX-like 1-4 are copper-dependent matrixmodifying enzymes [1]. The expression of LOX is elevated in many human cancers, including breast cancer and correlates with tissue hypoxia. The enzyme plays a critical role in breast cancer metastasis [2]. The goal of the current study was to target LOX with fluorescent and radiolabeled oligopeptides to visualize LOX in preclinical models of breast cancer.
Methods: mRNA expression of all 5 LOX family members was analyzed by gene expression microarray analysis on samples from 176 breast cancer patients. The peptidic substrate GGGDPKGGGGG was selected to target LOX [3]. The peptide was labeled with either FITC for confocal microscopy experiments or with the positron emitter fluorine-18 for molecular imaging in vivo using positron emission tomography (PET) (Figure 1). The preclinical breast cancer models utilized were the murine breast cancer cell line EMT-6 and xenografts of MCF-7 and MDAMB-231.
Results: Immunofluorescence with a LOX-specific antibody confirmed that LOX protein expression is enhanced in hypoxic EMT-6 cells. FITC-labeled oligopeptide binds to several cell compartments of EMT6 cells under hypoxic conditions. After injection of 18F-labeled oligopeptide, radioactivity uptake was visible in all three breast cancer models in vivo with SUV5min values of: 0.70±0.07 (n=3) in EMT-6, 0.57±0.01 (n=3) in MCF-7 and 0.68 (n=2) in MDA-MB-231. The following continuous washout of radioactivity led to SUV60min values of: 0.18±0.03 (n=3) in EMT-6, 0.14±0.02 (n=3) in MCF-7 and 0.13 (n=2) in MDA-MB-231. Tumor uptake was reduced by pre-dosing with the irreversible LOX inhibitor BAPN 4 h and 24 h prior to injection of the radiotracer.
Conclusions: These data support further investigations towards the development of LOX-binding peptides as molecular probes for imaging of LOX expression in breast cancer.
Acknowledgements: The access to the Alberta Cancer Foundation-supported CBCF Tumor Bank is well appreciated.
References
[1] Payne SL, et al (2007) J. Cell. Biochem.101, 1338-54.
[2] Erler JT, et al (2006) Nature 440, 1222-6.
[3] Nagan N and Kagan HM (1994) J. Biol. Chem. 269, 22366-71.

  • Poster
    21st International Symposium on Radiopharmaceutical Sciences (ISRS), 26.-31.05.2015, Columbia/Missouri, USA
  • Open Access Logo Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 58(2015), S204
    DOI: 10.1002/jlcr.3302_2

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Publ.-Id: 22088