Matrix metalloproteinase 26 proteolysis of the NH₂-terminal domain of the estrogen receptor β correlates with the survival of breast cancer patients

Estrogens have many cellular functions, including their interactions with estrogen receptors α and β (ERα and ERβ). Earlier, we determined that the estrogen-ER complex stimulates the transcriptional activity of the matrix metalloproteinase 26 (MMP-26) gene promoter. We then determined that ERβ is susceptible to MMP-26 proteolysis whereas ERα is resistant to the protease. MMP-26 targets the NH₂-terminal region of ERβ coding for the divergent NH₂-terminal A/B domain that is responsible for the ligand-independent transactivation function. As a result, MMP-26 proteolysis generates the COOH-terminal fragments of ERβ. Immunohistochemical analysis of tissue microarrays derived from 121 cancer patients corroborated these data and revealed an inverse correlation between the ERα-dependent expression of MMP-26 and the levels of the intact ERβ in breast carcinomas. MMP-26 is not expressed in normal mammary epithelium. The levels of MMP-26 are strongly up-regulated in ductal carcinoma in situ (DCIS). In the course of further disease progression through stages I to III, the expression of MMP-26 decreases. In contrast to many tumor-promoting MMPs, the expression of MMP-26 in DCIS correlated with a longer patient survival. Our data suggest the existence of an MMP-26-mediated intracellular pathway that targets ERβ and that MMP-26, a novel and valuable cancer marker, contributes favorably to the survival of the ERα/β-positive cohort of breast cancer patients.