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Breast cancer‐associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein

ADAM12 has recently emerged as a Candidate Cancer Gene in a comprehensive genetic analysis of human breast cancers. Three somatic mutations in ADAM12 were observed at significant frequencies in breast cancers: D301H, G479E and L792F. The first 2 of these mutations involve highly conserved residues in ADAM12, and our computational sequence analysis confirms that they may be cancer‐related. We show that the corresponding mutations in mouse ADAM12 inhibit the proteolytic processing and activation of ADAM12 in NIH3T3, COS‐7, CHO‐K1 cells and in MCF‐7 breast cancer cells. The D/H and G/E ADAM12 mutants exert a dominant‐negative effect on the processing of the wild‐type ADAM12. Immunofluorescence analysis and cell surface biotinylation experiments demonstrate that the D/H and G/E mutants are retained inside the cell and are not transported to the cell surface. Consequently, the D/H and G/E mutants, unlike the wild‐type ADAM12, are not capable of shedding Delta‐like l, a ligand for Notch receptor, at the cell surface, or of stimulating cell migration. Our results suggest that the breast cancer‐associated mutations interfere with the intracellular trafficking of ADAM12 and result in loss of the functional ADAM12 at the cell surface. © 2008 Wiley‐Liss, Inc.