ARID1A maintains the integrity of heterochromatin complex.

ARID1A interacts with TRIM28 independent of SWI/SNF.

The MSI status of indicated cell lines.

Dependency of DNA /RNA sensors in ARID1A-mediated antitumor immunity.

ARID1A remodels antitumor immunity.

Baseline clinicopathologic features of colorectal-cancer patients

Association between ARID1A expression level and clinicopathological characteristics in colorectal cancer patients

The top 30 ARID1A-interacting proteins

ARID1A deficiency provokes the derepression of endogenous satellite and retroelements to trigger innate immune responses.

Plasmids, reagents, and antibodies

ARID1A deficiency triggers satellites, ERVs and ISGs in multiple cell types.

The role of ARID1A on viral mimicry and immunogenicity depends on its interaction with TRIM28.

Inhibition of viral mimicry mitigates the effects of ARID1A deficiency.

Patients with estrogen receptor + (ER + , ESR1 + ) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1 , mirroring the 2 most common mutations seen in patients. ESR1 mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1 mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1 mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

TRIM28 but not SWI/SNF was essential for the effects of ARID1A on repression of satellites and retroelements.

ARID1A mutation types and counts across cancer types in TCGA

ARID1A deficiency affects the accessibility of heterochromatin.

RNA-sensor dependency underlies immune activation across murine tumor models.

Abstract Co-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. However, the molecular mechanisms promoting ER positivity within HER2+ cancers remains largely unknown. Here we show, across HER2+ transgenic mouse models the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2∆16 is detected across human HER2+ breast tumors and cell lines with higher levels correlating with increased expression of ER and downstream transcriptional targets. Notably, in human cell lines HER2∆16 expression is elevated upon acquired resistance to HER2-targeted therapy and can sensitize cells to the ER-antagonist tamoxifen. Overall, these findings offer valuable insights into the role of HER2∆16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.