Abstract P3-14-18: Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences

Abstract

Abstract Background & Hypothesis: The death rate is higher in Black (B) patients (40%), and, in particular, is two-fold higher among young B women (<50 years) compared to White (W) women with breast cancer. Aggressive breast cancer variants, like hormone receptor-negative and inflammatory breast cancer (IBC), contribute to a race-related survival gap and poor clinical outcomes in African American (AA) patients compared to Whites (W) in the United States. We previously identified the dominant role of XIAP in a tumor cell adaptive stress response (ASR) that promotes nuclear transcription factor (NFκB)-mediated proliferative, invasive, and immunosuppressive signaling in breast cancer progression. Our current work sought to address the urgent need to interrogate molecular mechanisms driving the disparity in both AA and IBC tumor biology by investigating gene expression differences between AA and White tumors and Triple-negative breast cancer (TNBC) and non-TNBC tumors, thereby identifying common genes which may be modifiable risk factors and targets that can be modulated for therapeutic benefits. Methods: We used The Cancer Genome Atlas (TCGA) breast cancer data to conduct a comparative analysis of the expression of 226 ASR genes in breast cancer molecular subtypes, normal-adjacent tissues, and in AA and W patients. The ASR gene list includes 101 XIAP-related, 11 NFκB targets, 10 MNK targets, 33 Oxidative Stress Response (OSR)-related, 13 TGFβ-related, 6 JAG1-Notch targets, and 52 immune-related, in addition to 14 genes that belong to more than one ASR set. In the present study, we focused on primary tumor samples [1090 Primary Solid Tumor] and normal tissue samples adjacent to the tumors [113 Solid Tissue Normal]. Within these, our sample set included 559 lumA, 207 lumB, 82 Her2, 190 Basal, and 40 Normal-like. Racial designations in TCGA are based on patient self-identification. In the present study, the race-related analysis focused on AA and W breast cancer patient datasets from TCGA (179 AA and 744 W). It is important to note that among the 113 Normal-adjacent samples, there are 105 W and only 6 AA samples. Results: Analysis of the ASR gene score in different Breast cancer subtypes revealed that ASR genes associated with oxidative stress and immune response pathways score highly in the basal breast cancer subtype. We also observed differential scores between samples of AA or W. The differential gene expression analysis identified 46-88 genes in the ASR set to be differentially expressed (≥2 fold-change and adjusted p-value <0.05) in breast cancer subtypes when comparing each subtype to normal-adjacent tissue or comparing the subtypes to each other. Pathway analysis of the enriched genes revealed the involvement of the cell cycle, the DNA damage response, the signal transduction, and the regulation of cell death-related processes. Moreover, on average, 20% of the ASR genes showed race-related differential expression. Furthermore, a number of ASR that were differentially expressed in breast cancer subtypes and significantly associated (hazard ratio >1.5 and p-value <0.05) with AA and/or W patient survival. For example, CDC45, MCM3, and CDKN2D were uniquely associated with poor survival in AA, but not in W. Conclusion: Within invasive breast cancer, factors that regulate tumor cell ASR reveal subtype and race-specific differences in expression. Understanding their function and downstream signaling will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer outcomes and have the potential to reveal race-related biomarkers and therapeutic targets. Support: NCI-P20 NCCU-Duke Cancer Disparities Translational Research Partnership (SP; GRD, KPW, JF), DoD-W81XWH-17-1-0297 (GRD), Duke Bridge Funds (GRD). Citation Format: Muthana Al Abo, Larisa Gearhart-Serna, Steven Van Laere, Jennifer Freedman, Steven Patierno, Eun-Sil Hwang, Savitri Krishnamurthy, Kevin Williams, Gayathri Devi. Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-18.