title: Matrix metalloproteinase 26 proteolysis of the NH2-terminal domain of the estrogen receptor beta correlates with the survival of breast cancer patients.
abstract: Estrogens have many cellular functions, including their interactions with estrogen receptors alpha and beta (ERalpha and ERbeta). 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 ERbeta is susceptible to MMP-26 proteolysis whereas ERalpha is resistant to the protease. MMP-26 targets the NH(2)-terminal region of ERbeta coding for the divergent NH(2)-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 ERbeta. Immunohistochemical analysis of tissue microarrays derived from 121 cancer patients corroborated these data and revealed an inverse correlation between the ERalpha-dependent expression of MMP-26 and the levels of the intact ERbeta 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 ERbeta and that MMP-26, a novel and valuable cancer marker, contributes favorably to the survival of the ERalpha/beta-positive cohort of breast cancer patients.
authors.affiliation: The Burnham Institute, La Jolla, California 92037, USA.
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Savinov
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Susan
authors.initials: S
authors.lastname: Kennedy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Rozanov
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053505:Matrix Metalloproteinases, Secreted; D009367:Neoplasm Staging; D015996:Survival Rate
chemical_list: D047629:Estrogen Receptor beta; C410599:MMP26 protein, human; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted