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

Alexei Y. Savinov, Albert G. Remacle, Vladislav S. Golubkov, Maryla Krajewska, Susan Kennedy, Michael J. Duffy, Dmitri V. Rozanov, Stan Krajewski, Alex Y. Strongin

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2716-2724
Number of pages9
JournalCancer Research
Volume66
Issue number5
DOIs
StatePublished - Mar 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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