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J. Biol. Chem., Vol. 283, Issue 12, 7438-7444, March 21, 2008

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Alterations of BRMS1-ARID4A Interaction Modify Gene Expression but Still Suppress Metastasis in Human Breast Cancer Cells^*

Douglas R. Hurst¹, Yi Xie¹, Kedar S. Vaidya, Alka Mehta, Blake P. Moore, Mary Ann Accavitti-Loper^¶, Rajeev S. Samant^||, Ritu Saxena, Alexandra C. Silveira, and Danny R. Welch^**2

From the Departments of Pathology, Cell Biology, and ^**Pharmacology/Toxicology, the Comprehensive Cancer Center, and the ^¶Epitope Recognition and Immunoreagent Core Facility, University of Alabama, Birmingham, Alabama 35294 and the ^||Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36688

The BRMS1 metastasis suppressor interacts with the protein AT-rich interactive domain 4A (ARID4A, RBBP1) as part of SIN3·histone deacetylase chromatin remodeling complexes. These transcriptional co-repressors regulate diverse cell phenotypes depending upon complex composition. To define BRMS1 complexes and their roles in metastasis suppression, we generated BRMS1 mutants (BRMS1^mut) and mapped ARID4A interactions. BRMS1^L174D disrupted direct interaction with ARID4A in yeast two-hybrid genetic screens but retained an indirect association with ARID4A in MDA-MB-231 and -435 human breast cancer cell lines by co-immunoprecipitation. Deletion of the first coiled-coil domain (BRMS1^CC1) did not disrupt direct interaction in yeast two-hybrid screens but did prevent association by co-immunoprecipitation. These results suggest altered complex composition with BRMS1^mut. Although basal transcription repression was impaired and the pro-metastatic protein osteopontin was differentially down-regulated by BRMS1^L174D and BRMS1^CC1, both down-regulated the epidermal growth factor receptor and suppressed metastasis in MDA-MB-231 and -435 breast cancer xenograft models. We conclude that BRMS1^mut, which modifies the composition of a SIN3·histone deacetylase chromatin remodeling complex, leads to altered gene expression profiles. Because metastasis requires the coordinate expression of multiple genes, down-regulation of at least one important gene, such as the epidermal growth factor receptor, had the ability to suppress metastasis. Understanding which interactions are necessary for particular biochemical/cellular functions may prove important for future strategies targeting metastasis.

Received for publication, November 19, 2007 , and in revised form, January 9, 2008.

^* This work was supported by United States Public Health Service Grants CA87728 (to D. R. W.) and F32CA113037 (to D. R. H.), a grant from the National Foundation for Cancer Research Center for Metastasis Research (to D. R. W.), and Susan G. Komen for the Cure Grants PDF1122006 (to K. S. V.) and BCTR0503488 (to R. S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, 1670 University Blvd., Rm. VH-G019, Birmingham, AL 35294-0019. Tel.: 205-934-2961; Fax: 205-975-1126; E-mail: DanWelch{at}uab.edu.

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