Abstract IA012: Reducing disparities in breast cancer mortality through the identification of novel targets in triple-negative breast cancer
Authors: Cottrell Kyle , Kung Pat , Ryu Sua , Maggi Leonard , Kuzmicki Catherine , Kladney Raleigh , Yiu Ling , Colditz Graham , Weber Jason D. 
Published: January 2023

Abstract
Triple-negative breast cancer (TNBC) remains a challenge to clinicians, laboratory investigators, and patients due to its disproportionate number of breast cancer deaths and its lack of an established therapeutic target. Numerous studies have identified potential novel mutational gene targets in TNBC, but single-agent therapeutics have lacked substantial impact in TNBC. Novel effective therapies are desperately needed. Alongside these therapies, we need accurate biomarkers that can be used to predict which patients will respond. We find that the ARF tumor suppressor expression is lost alongside p53 mutation in 60% of TNBC. ARF is the key player in sensing cellular oncogene-induced stress, such as signals emanating from oncogenic Ras and Myc alleles. ARF suppresses tumor formation in both p53-dependent and -independent mechanisms by interacting with proteins within the cell nucleolus. Our findings have advanced the premise that the p53-indendent functions of ARF are critical to preventing epithelial-based cancers. Our data show that mammary epithelial cells rapidly induce ARF expression in vitro and in vivo upon loss of functional p53. This induced ARF suppresses mammary tumor formation in vivo, wherein loss of both p53 and ARF dramatically accelerates tumorigenesis. This is consistent with our evidence that ARF and p53 function are concomitantly lost in TNBC. Potentially stemming from the dual loss of ARF and p53, we have observed that type I IFN signaling is elevated in TNBC. Our laboratory and others have shown that cancer cell lines, including those derived from TNBC, with elevated IFN signaling are dependent on the RNA deaminase ADAR1. Loss of ADAR1 in these cells leads to hyperactivation of the type I IFN pathway and cell death. We hypothesized that loss of ARF and p53 results in elevated type I IFN signaling and sensitizes cells to ADAR1 depletion. Beyond the potential genetic interaction between ARF-loss and ADAR1-dependency in TNBC, recent work from our lab has revealed that ARF and ADAR1 physically interact in cells lacking functional p53. We find that ARF can fully titrate much of the cellular ADAR1 into ARF complexes. Additionally, TNBC cells, but not non-TNBC cells, are sensitive to ADAR1 knockdown. Sensitivity to ADAR1 depletion appears to require type I IFN signaling and subsequent PKR activation. Analysis of primary human TNBC showed a marked separation of IFN signaling and ADAR1 localization/function between African American and Caucasian TNBC patients, suggesting that this pathway may serve as a functional marker of African American TNBC.
Citation Format: Kyle Cottrell, Pat Kung, Sua Ryu, Leonard Maggi, Catherine Kuzmicki, Raleigh Kladney, Ling Yiu, Graham Colditz, Jason D. Weber. Reducing disparities in breast cancer mortality through the identification of novel targets 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 IA012.