Abstract C055: CARM1-mediated BAF155 methylation promotes metastasis and is targetable to reduce disparate mortality in triple negative breast cancer

Abstract

Abstract Breast cancer (BC) has disparate mortality rates between African American (AA) and non-Hispanic White (White) individuals. Despite an overall lower incidence of BC, AA women are 41% more likely to die from BC than White women. BC can be biochemically classified based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), or classified by gene expression profiling as luminal, HER2+ and basal-like types. A recent large cohort analysis of nearly 200,000 patients found that AA women had a nearly three-fold increased risk of triple-negative BC, a subtype of basal-like BC that is associated with poor prognosis and metastasis. Although an increasing number of studies compare breast cancer molecular features and gene expression differences between breast tumors from AA and White patients, the underlying biological mechanisms contributing to this disparity are still unknown. We studied the oncogenic roles of coactivator associated arginine methyltransferase 1 (CARM1) and that is highly expressed in TNBC and CARM1 was overexpressed in AA patients through TCGA analysis. We have identified BRG1-Associated Factor 155 (BAF155), a component of SWI/SNF chromatin remodeling complex, is specifically methylated by CARM1. Herein, we discovered the dual roles of methylated-BAF155 (me-BAF155) in promoting tumor metastasis: activation of super-enhancer-addicted oncogenes by recruiting BRD4, and repression of interferon α/γ pathway genes to suppress host immune response. Pharmacological inhibition of CARM1 and BAF155 methylation not only abrogated the expression of an array of oncogenes, but also boosted host immune responses by enhancing the activity and tumor infiltration of cytotoxic T cells. Moreover, strong me-BAF155 staining was detected in circulating tumor cells from metastatic cancer patients. Despite low cytotoxicity, CARM1 inhibitors strongly inhibited TNBC cell migration in vitro, and growth and metastasis in vivo. These data suggest that me-BAF155 is a marker for detecting metastasis patients in AA women and CARM1 is an important epigenetic target for treatment of TNBC to reduce mortality in AA women. Citation Format: Eui-Jun Kim, Peng Liu, Yidan Wang, Irene M. Ong, Wei Xu. CARM1-mediated BAF155 methylation promotes metastasis and is targetable to reduce disparate mortality in triple negative breast cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C055.