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Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer.


ABSTRACT: The transcription factors Runx2 and estrogen receptor-alpha (ERalpha) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERalpha strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx2's amino acids 417-514, encompassing activation domain 3 and the nuclear matrix targeting sequence, were sufficient for interaction with ERalpha's DNA-binding domain. As a consequence of the interaction, Runx2's transcriptional activation activity was strongly repressed, as shown by reporter assays in COS7 cells, breast cancer cells, and late-stage MC3T3-E1 osteoblast cultures. Metaanalysis of gene expression in 779 breast cancer biopsies indicated negative correlation between the expression of ERalpha and Runx2 target genes. Selective ER modulators (SERM) induced ERalpha-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ERalpha may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ERalpha ligands offers new avenues in selective ER modulator evaluation and development.

SUBMITTER: Khalid O 

PROVIDER: S-EPMC2613062 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer.

Khalid Omar O   Baniwal Sanjeev K SK   Purcell Daniel J DJ   Leclerc Nathalie N   Gabet Yankel Y   Stallcup Michael R MR   Coetzee Gerhard A GA   Frenkel Baruch B  

Endocrinology 20080828 12


The transcription factors Runx2 and estrogen receptor-alpha (ERalpha) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERalpha strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx  ...[more]

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