Mutations in the NH 2 -terminal regulatory domain of the ␤-catenin gene lead to aberrant stabilization and accumulation of the protein and increased TCF/LEF-dependent transcription. Although these mutations are common in some cancers, they are infrequent in prostate and breast cancer. We have found that metastatic prostate cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed a novel M r 75,000 proteolytic fragment of ␤-catenin (␤-cat 75 ). ␤-Cat 75 was also

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... pressed in multiple prostate and breast cancer cell lines and was closely associated with the activity of the calcium-dependent protease, calpain. In a prostate cancer cDNA microarray, m-calpain RNA levels were found to be significantly increased in metastatic disease compared with normal prostate. We showed calpain-dependent generation of ␤-cat 75 in cell culture and in vitro. Molecular mapping revealed that calpain cleavage removed the NH 2 -terminal regulatory domain of the ␤-catenin protein. Treatment of MCF-7 cells with ionomycin led to increased accumulation of ␤-cat 75 in the nucleus and TCF-dependent transcriptional activity. Overexpression of a similar ␤-catenin fragment that lacks the NH 2 -terminal 132 amino acids and has transforming potential activated TCF-dependent transcription. Given the low frequency of mutationinduced activation of ␤-catenin in prostate and breast cancers, proteolytic cleavage of ␤-catenin by calpain may represent a novel mechanism by which the protein is activated during tumorigenesis.