title: 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.
authors.affiliation: Department of Urology, Preventive Medicine, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Khalid
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Baniwal
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Purcell
authors.forename: Nathalie
authors.initials: N
authors.lastname: Leclerc
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel