PT  - JOURNAL ARTICLE
AU  - Michael Mosley
AU  - James Knight
AU  - Albrecht Neesse
AU  - Patrick Michl
AU  - Manuela Iezzi
AU  - Veerle Kersemans
AU  - Bart Cornelissen
TI  - Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer
AID  - 10.2967/jnumed.114.152496
DP  - 2015 May 01
TA  - Journal of Nuclear Medicine
PG  - 745--751
VI  - 56
IP  - 5
4099  - http://jnm.snmjournals.org/content/56/5/745.short
4100  - http://jnm.snmjournals.org/content/56/5/745.full
SO  - J Nucl Med2015 May 01; 56
AB  - The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C-terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate whole-body quantitative SPECT imaging of preneoplastic breast cancer tissue using 111In-labeled cCPE. Methods: cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow 111In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4–expressing MDA-MB-468 and SQ20b cells, compared with claudin-4–negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4–expressing breast cancer lesions. Results: The uptake of 111In-cCPE.GST in claudin-4–positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in 111In-GST or claudin-4–negative HT1080 tumors (6.72 ± 0.18 vs. 3.88 ± 1.00 vs. 2.36 ± 1.25 percentage injected dose per gram [%ID/g]; P < 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4–positive, and 111In-cCPE.GST uptake was 3.2 ± 0.70 %ID/g, significantly higher than 111In-GST (1.00 ± 0.60 %ID/g; P < 0.05). Mammary fat pads in mice aged 80 d bore claudin-4–positive aplastic lesions and accumulated 111In-cCPE.GST (3.17 ± 0.51 %ID/g) but not 111In-GST (0.99 ± 0.39 %ID/g; P < 0.001). Conclusion: Taken together, 111In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer.