Detection of Canonical Hedgehog Signaling in Breast Cancer by131-Iodine-Labeled Derivatives of the Sonic Hedgehog Protein

الملخص EN

Activation of hedgehog (HH) pathway signaling is observed in many tumors.

Due to a feedback loop, the HH receptor Patched (PTCH-1) is overexpressed in tumors with activated HH signaling.

Therefore, we sought to radiolabel the PTCH-1 ligand sonic (SHH) for detection of cancer cells with canonical HH activity.

Receptor binding of 131I-SHH was increased in cell lines with high HH pathway activation.

Our findings also show that PTCH-1 receptor expression is decreased upon treatment with HH signaling inhibitors, and receptor binding of 131I-SHH is significantly decreased following treatment with cyclopamine.

In vivo imaging and biodistribution studies revealed significant accumulation of 131I-SHH within tumor tissue as compared to normal organs.

Tumor-to-muscle ratios were approximately 8 : 1 at 5 hours, while tumor to blood and tumor to bone were 2 : 1 and 5 : 1, respectively.

Significant uptake was also observed in liver and gastrointestinal tissue.

These studies show that 131I-SHH is capable of in vivo detection of breast tumors with high HH signaling.

We further demonstrate that the hedgehog receptor PTCH-1 is downregulated upon treatment with hedgehog inhibitors.

Our data suggests that radiolabeled SHH derivatives may provide a method to determine response to SHH-targeted therapies.