Annually in the U.S., 250,000 women develop breast cancer, and 40,000 die from it. Most have a “sporadic” rather than inherited etiology, therefore attention has focused on identifying “driver” genes that are spontaneously mutated in cancers. The SWI/SNF chromatin remodeling complex member ARID/A is one of the most frequently altered genes in several cancers, including breast, but a causal role has not been demonstrated. Using the Chao.s3 mouse model of sporadic breast cancer, we found that nearly all mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid/a allele, while the remaining intact allele was downregulated. We were able to reactivate the epigenetically silenced allele by treatment with the cytosine methyltransferase inhibitor 5-azacytidine, and found that restoration of Arid/a expression in a Chaos3 mammary tumor line impaired its tumorigenicity,indicating that ARID1A insufficiency is crucial thr tumor maintenance. These results provide an opportunity for therapeutic intervention in ARID IA-deficient human breast cancer subtypes. In this project, we propose to utilize CRISPR-activation (CRISPRa) technology to specifically reactivate expression of silenced, but intact, Arid/a alleles in Chao.s3 tumor cells. Directed epigenetic modification and transcriptional activators modalities will be evaluated for efficacy of gene activation and tumor suppression following transplantation of tumor lines into mice. Success in these proof-in-principle studies would form the groundwork for developing precision treatment for the >25% of ARIDIA-deficient breast cancers. Additional experiments using conditional knockout mice will address the roles of Arid/a and another commonly deleted gene. Nil, in mammary tumor initiation and maintenance, so as to delineate the genetic driver events in certain breast cancers, and to develop combination therapies.