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Matrix Metalloproteinase 26 Proteolysis of the NH₂-Terminal Domain of the Estrogen Receptor ß Correlates with the Survival of Breast Cancer Patients

¹ The Burnham Institute, La Jolla, California; ² Royal Victoria Eye and Ear Hospital, Dublin, Ireland; and ³ Department of Surgery, St. Vincents's University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

Requests for reprints: Alex Y. Strongin and Stan Krajewski, Cell Adhesion and Extracellular Matrix Biology, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-713-6271; Fax: 858-646-3192; E-mail: strongin{at}burnham.org and stan{at}burnham.org.

Estrogens have many cellular functions, including their interactions with estrogen receptors and ß (ER and ERß). 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 ERß is susceptible to MMP-26 proteolysis whereas ER is resistant to the protease. MMP-26 targets the NH₂-terminal region of ERß 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 ERß. Immunohistochemical analysis of tissue microarrays derived from 121 cancer patients corroborated these data and revealed an inverse correlation between the ER-dependent expression of MMP-26 and the levels of the intact ERß 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 ERß and that MMP-26, a novel and valuable cancer marker, contributes favorably to the survival of the ER/ß–positive cohort of breast cancer patients. (Cancer Res 2006; 66(5): 2716-24)

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