Loss of tumor suppressors is a hallmark of poor prognosis of cancer. We show that matrix metalloproteinase 12 (MMP12) is up regulated in 4T1 mammary cancer and moonlights intracellular as a functional protease after crossing the plasma membrane. Stable knockdown of MMP12 resulted in a lower incidence of lung metastasis, and increased survival post-primary tumor resection. In contrast, in Mmp12-/- mice stromal and macrophage MMP12 had no effect on tumor growth or survival. Using TAILS N-terminomics, novel in vivo intracellular substrates of MMP12 were identified including the tumor suppressor tyrosine-protein kinase SYK. SYK is associated with reductions in tumor cell migration and metastatic potential of breast cancer cells. We found that tumor cell MMP12 was localised intracellular and often within the nucleus. Indeed, exogenous MMP12 rapidly translocated across the plasma membrane whereupon it cleaved and inactivated SYK leading to enhanced cell migration and metastasis of breast cancer cells. Treatment of murine and human breast cancer cells with a selective MMP12 inhibitor rescued SYK protein levels. In over 100 different human breast cancer tumors we found that only malignant tumors were associated with a highly elevated MMP12 to SYK ratio. Thus, intracellular cleavage and inactivation of the SKY tumor suppressor is associated with worsened cancer prognosis.