The scaffold attachment factor/nuclear matrix protein SAFB maps to a locus with extremely high loss of heterozygosity in human breast cancer. Its expression is also reduced in many breast cancers, and in a xenograft model of antiestrogen resistance. Recently we discovered that SAFB binds directly to the estrogen receptor (ER), and functions as an ER corepressor. SAFB binding to ER is increased by the antiestrogen tamoxifen, and SAFB can enhance tamoxifen-mediated repression of ER. The repressive effect of SAFB on ER activity appears to involve chromatin remodeling, since repression is relieved by the histone deacetylase (HDAC) inhibitor trichostatin A. Supporting this, we have recently mapped an independent repression domain in SAFB that binds proteins with LIM and RING domains which have been shown to be involved in chromatin-mediated regulation of gene expression.We therefore propose to define the function of SAFB in regulating ER function, making use of our unique model systems that will elucidate specific SAFB effects upon ER in vitro and in vivo, and the role of loss of SAFB in the onset of antiestrogens resistance. Specifically, we will ask: 1) Which classes of endogenous estrogen-regulated genes are affected by SAFB, and how does this translate to growth effects? We will investigate the growth and gene expression effects of inducible changes in SAFB levels in a unique model, comparing ER-negative MCF-7-derived cells (C4-12) vs. C4-12 cells with restored functional ER (C4-I2ER-HA). 2) Does SAFB-mediated repression of ER involve chromatin remodeling? Because of the evidence implicating chromatin remodeling in the ER-repressive effects of SAFB, we will investigate the involvement of interaction with HDACs and other proteins implicated in modulating chromatin structure. 3) Is SAFB expression critical for the development of estrogen-responsive tissues, and is this reflected by altered expression of estrogen target genes in vivo? We will address these issues in SAFB-null mice. 4) Is SAFB involved in the development of antiestrogen resistance in breast cancer cells? Because SAFB enhances the ability of antiestrogens like tamoxifen to inhibit ER-mediated transcription, and SAFB is reduced in a xenograft model of tamoxifen resistance, we will test directly whether decreased SAFB levels change expression of estrogen-regulated genes in this model and enhance the onset of resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097213-05
Application #
7087942
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2002-08-01
Project End
2009-06-30
Budget Start
2006-08-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$261,595
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Jiang, Shiming; Katz, Tiffany A; Garee, Jason P et al. (2015) Scaffold attachment factor B2 (SAFB2)-null mice reveal non-redundant functions of SAFB2 compared with its paralog, SAFB1. Dis Model Mech 8:1121-7
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Hernandez-Hernandez, J Manuel; Mallappa, Chandrashekara; Nasipak, Brian T et al. (2013) The Scaffold attachment factor b1 (Safb1) regulates myogenic differentiation by facilitating the transition of myogenic gene chromatin from a repressed to an activated state. Nucleic Acids Res 41:5704-16
Oesterreich, Steffi; Brufsky, Adam M; Davidson, Nancy E (2013) Using mice to treat (wo)men: mining genetic changes in patient xenografts to attack breast cancer. Cell Rep 4:1061-2
Casa, Angelo J; Potter, Adam S; Malik, Simeen et al. (2012) Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. Breast Cancer Res Treat 132:61-73
Garee, Jason P; Meyer, Rene; Oesterreich, Steffi (2011) Co-repressor activity of scaffold attachment factor B1 requires sumoylation. Biochem Biophys Res Commun 408:516-22
Malik, Simeen; Jiang, Shiming; Garee, Jason P et al. (2010) Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM. Mol Cell Biol 30:399-412
Hammerich-Hille, Stephanie; Kaipparettu, Benny A; Tsimelzon, Anna et al. (2010) SAFB1 mediates repression of immune regulators and apoptotic genes in breast cancer cells. J Biol Chem 285:3608-16

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