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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.

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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