Abstract 1458: Arid4b: A germline breast cancer progression modifier gene

Abstract

Abstract Our laboratory's research focuses on the role of host genetics in breast cancer metastasis. The MMTV-PyMT transgenic mouse model exhibits varying metastatic efficiency to the lungs when transgenic mice in an FVB background are bred to other strains such as DBA and AKR. Combining quantitative measurement of metastasis with genetic mapping studies of the AKXD recombinant inbred panel of mice has allowed us to determine quantitative trait loci (QTLs) that affect metastatic efficiency. My work has focused on the potential role of Arid4b in breast cancer tumorigenesis and metastasis. Arid4b is a component of the mSin3a histone deacetylase complex, which has an established role in breast cancer progression, and Arid4b is a candidate gene underlying a metastasis QTL peak we have identified on mouse chromosome 13. Sequencing revealed a high density of non-synonymous SNPs between the AKR and DBA alleles in exon 22, which encodes a C-terminal region of the Arid4b protein that is known to mediate interaction with the mSin3a HDAC complex. We have recently discovered that Arid4b binds another protein that our laboratory has implicated in metastasis susceptibility, the transcriptional elongation regulator Bromodomain 4 (Brd4), and we are currently using co-IPs and proteomics strategies such as tandem affinity purification to identify other proteins that may bind differentially to the AKR or DBA Arid4b proteins. In orthotopic implantation assays, cells ectopically expressing the DBA allele of Arid4b formed larger primary tumors compared to cells expressing the AKR allele, and western blots using an Ab specific for dimethylated histone H3 lysine 27 suggest that the mechanism of Arid4b action may involve modification of chromatin structure. Arid4b is also alternately spliced, and a second isoform lacks part of a conserved Chromo domain that is predicted to bind methylated histone tails. We are currently investigating the consequences of ectopic expression of the multiple alleles and isoforms of Arid4b in vivo using orthotopic implantation assays. It is likely that both the alternate splicing of the Chromo domain and the allelic variation in the C-terminal domain modulate an epigenetic influence of Arid4b on tumorigenesis and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1458. doi:10.1158/1538-7445.AM2011-1458