Abstract B035: Identification of a tumor cell adaptive stress response signaling pathway, which drives aggressive breast cancer phenotype and therapeutic resistance, in African American patients with locally advanced breast cancer subtypes
Authors: Devi Gayathri R , Al Abo Muthana , Gearhart-Serna Larisa , Geradts Joseph , McCall Shannon J , Krishnamurthy Savitri 
Published: September 2020

Abstract
Introduction: The higher incidence of biologically aggressive and treatment-resistant breast cancer (BCa) subtypes, which includes triple negative (TN), basal, and inflammatory breast cancer (IBC), contributes to worse survival outcomes in African American/AA patients, 42% higher death rate compared to White BCa. Amongst locally advanced BCa, IBC is a model of aggressive, most lethal, frequently basal/TN, accounting for 10% AA BCa and disparity in outcomes exist after adjusting for socioeconomic and diagnosis factors. IBC exhibits a unique phenotype wherein malignant cells do not form solid masses and instead, present as hyperproliferative tumor cell clusters, termed tumor emboli, in the skin and lymphatics. Our key finding was the identification of a tumor cell adaptive stress response pathway linking the mitogen activated ser/thr kinase/MNK, X-linked inhibitor of anti-apoptotic protein, XIAP, and nuclear transcription factor, NFkB, mediated proliferative, invasive and immunosuppressive signaling. Our goal was to determine the role of the adaptive stress response pathway, which we have identified to contribute to aggressiveness of TNBC and IBC, in AA breast tumor biology. Methods: Expression of MNK, XIAP and NFkB target gene sets, a 40-gene oxidative stress response that correlates with response to cell death stimuli and a 79-gene IBC signature (identified from comparative analysis of IBC and non-IBC biospecimens) were evaluated in The Cancer Genome Atlas (TCGA) breast cancer datasets (1109 tumor; 113 normal) stratified according to race and molecular subtypes (luminal A, B, Her2, basal). The mean expression for each gene in these signatures were also assessed among different subtypes and race using R. Gene Ontology (GO) analysis was performed using GATHER online tool. XIAP immunohistochemistry (IHC) conducted in BCa samples (n=93) from Duke and MDACC biorepositories. Results: TCGA analysis of the IBC-related signatures identified genes differentially expressed (&gt;2-fold change; Wilcoxon rank sum test, FDR&lt;0.05) among BCa subtypes and between AA vs White within a subtype. Additionally, the oxidative stress response metagene was significantly upregulated in AA basal (p=0.037) whereas there were fewer differences in immune-related genes within AA subtypes suggesting attenuated immune response. IHC, to date, shows high XIAP in high grade, ER-negative and in majority of AA BCa and in IBC samples independent of molecular subtypes and grade. Conclusions: We report a heightened adaptive stress response gene signature and identify genes in the MNK:XIAP:NFkB pathway and IBC-related signatures in AA BCa, suggesting potential biomarkers and drug discovery targets. High XIAP expression in high grade BCa, frequent in AA patients, is of therapeutic relevance as XIAP, the most potent caspase inhibitor, is linked to chemo- and immunotherapy resistance and XIAP inhibitors are in clinical trials. Supported by DOD-Breakthrough-W81XWH-17-1-0297; Duke SOM bridge funds; NCI-1P20-CA202925-01A12.
Citation Format: Gayathri R Devi, Muthana Al Abo, Larisa Gearhart-Serna, Joseph Geradts, Shannon J McCall, Savitri Krishnamurthy. Identification of a tumor cell adaptive stress response signaling pathway, which drives aggressive breast cancer phenotype and therapeutic resistance, in African American patients with locally advanced breast cancer subtypes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B035.