Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been functionally demonstrated in compound knockout mice. In my primary thesis work, I have found genetic and functional evidence that Arid1a is a bona fide breast cancer tumor suppressor, using the Mcm4chaos3 mouse model of sporadic mammary carcinogenesis. Nearly all mammary tumors that form in these mice contain a deletion removing one Arid1a allele, while the remaining intact allele is silenced or downregulated in many cases. The epigenetically silenced allele could be reactivated by treatment with the cytosine methyltransferase inhibitor 5-azacytidine. Restoration of Arid1a expression in a Chaos3 mammary tumor line greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these tumors. Transcriptome analysis of tumor cells before and after re-introduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, suggestively in a TRP53-dependent manner. These preliminary results provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer. My current thesis work involves the generation of a mammary-specific conditional knock-out mouse model of Arid1a, which will help determine whether loss of ARID1A is an initiating driver of mammary tumors. I am also attempting to induce expression of the remaining Arid1a allele present in multiple Chaos3 mammary tumor cell lines in a locus-specific manner, using CRISPR-activation (CRISPRa) technology. If successful, this would indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes.