Abstract 2371: Arid4b is a potential 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 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 that has a known role in breast cancer progression and is a candidate gene underlying a metastasis QTL peak we have identified on mouse chromosome 13. In two independent mouse breast cancer cell lines, Met-1 and PyMT-luc, stable expression of the AKR (high metastatic strain) allele caused significantly larger primary tumor growth than the DBA (low metastatic strain) allele following orthotopic implantation into the mammary fat pads of syngeneic hosts. In Met-1 cells we detected lung surface metastases in the AKR cohort but not in the DBA cohort. We are in the process of performing functional analyses to determine a mechanism of action whereby Arid4b polymorphisms influence tumorigenesis and metastasis. Sequencing has 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 are currently using co-IPs and proteomics strategies, such as tandem affinity purification, to identify proteins that bind differentially to the AKR or DBA Arid4b proteins. Arid4b is also alternately spliced and cells ectopically expressing the shorter isoform 2 formed significantly larger tumors in our orthotopic model compared to cells expressing the full-length isoform 1. Interestingly, the alternately spliced exon encodes part of a conserved Chromodomain, which is known to mediate binding of other Chromodomain containing proteins such as HP1 to modified histone tails. Western blots using an Ab specific for dimethylated histone H3 lysine 27 suggest a potential role of Arid4b in modifying chromatin structure. It is likely that both the alternate splicing of the Chromo domain and the allelic variation in the C-terminal domain modulate the epigenetic influence of Arid4b on tumorigenesis and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2371.