This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khalid, O. Articles by Frenkel, B. Search for Related Content PubMed PubMed Citation Articles by Khalid, O. Articles by Frenkel, B.

Modulation of Runx2 Activity by Estrogen Receptor-: Implications for Osteoporosis and Breast Cancer

From Departments of Urology (O.K., Y.G., G.A.C.), Preventive Medicine (O.K., G.A.C.), Biochemistry and Molecular Biology (S.K.B., D.J.P., N.L., M.R.S., B.F.), and Orthopedic Surgery (B.F.), Norris Cancer Center (O.K., D.J.P., Y.G., M.R.S., G.A.C.), Institute for Genetic Medicine (S.K.B., N.L., Y.G., B.F.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Baruch Frenkel, D.M.D., Ph.D., USC/IGM, 2250 Alcazar Street, CSC-250, Los Angeles, California 90033. E-mail: frenkel{at}usc.edu; or Gerhard A. Coetzee, Ph.D., USC/Norris Cancer Center, NOR 6411, 1441, Eastlake Avenue, Los Angeles, California 90033. E-mail: coetzee{at}usc.edu.

The transcription factors Runx2 and estrogen receptor- (ER) 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 ER 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 ER’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 ER and Runx2 target genes. Selective ER modulators (SERM) induced ER-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ER may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ER ligands offers new avenues in selective ER modulator evaluation and development.

This article has been cited by other articles:

				S. K. Baniwal, O. Khalid, D. Sir, G. Buchanan, G. A. Coetzee, and B. Frenkel Repression of Runx2 by Androgen Receptor (AR) in Osteoblasts and Prostate Cancer Cells: AR Binds Runx2 and Abrogates Its Recruitment to DNA Mol. Endocrinol., August 1, 2009; 23(8): 1203 - 1214. [Abstract] [Full Text] [PDF]