mSWI/SNF Component ARID1A Mediates Breast Cancer Treatment Response

Although most breast cancers are driven by estrogen receptor (ER) signaling and drugs targeting the ER pathway are often effective, de novo or acquired resistance is still problematic, prompting efforts to pinpoint factors that influence ER-related pathways. Using a genome-wide CRISPR screen in a breast cancer cell line, Nagarajan and colleagues found that ARID1A, encoding the BAF (also known as mSWI/SNF)-complex component AT-rich interactive domain-containing protein 1A, and some other BAF component–encoding genes were involved in response to treatment. Specifically, the results of the screen implied that the BAF complex was required for response to treatment with the ER modulator tamoxifen or the ER degrader fulvestrant, but that loss of the BAF complex sensitized cells to treatment with JQ1, which inhibits a potential therapeutic target (BRD4) in ER⁺ breast cancer. Chromatin immunoprecipitation with sequencing analyses showed that more than 78% of ARID1A binding sites overlapped with those of ER, the pioneer transcription factor FOXA1, or both. Notably, the binding of ARID1A to these sites was not dependent on ligand-induced ER recruitment. Mouse xenograft experiments revealed that ARID1A knockout in tumor cells reduced the antitumor activity of tamoxifen and resulted in increased tumor growth even in the absence of treatment. Further experiments showed that ARID1A is able to regulate ER-target genes and may even be part of the ER transcriptional complex, and the role of FOXA1 in the process was revealed to be recruitment of ARID1A to chromatin. Mechanistically, ARID1A participated in recruitment of the histone deacetylase HDAC1 to target sites, resulting in decreased acetylation of H4 and restricted BRD4 recruitment, leading to decreased basal cell proliferation rates. These findings demonstrate how the BAF component ARID1A is recruited to ER-binding sites by FOXA1 prior to ER binding and that ARID1A contributes to transcriptional repression via recruitment of HDAC1. Because ARID1A mutations are present in approximately 5% of primary breast cancers and approximately 12% of metastatic breast cancers, deeper understanding of this pathway is needed.

Nagarajan S, Rao SV, Sutton J, Cheeseman D, Dunn S, Papachristou EK, et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat Genet 2020 Jan 6 [Epub ahead of print].

• ©2020 American Association for Cancer Research.