Abstract B44: Immune pathway dysregulations in inflammatory breast cancer health disparity
Authors: Devi Gayathri R. , Hwang Eun-Sil Shelley , Stewart John , Morse Michael A. , Laere Steven Van 
Published: March 2017

Background: Inflammatory breast cancer (IBC) is a distinct, aggressive and the most lethal form of breast cancer. Furthermore, data from population-based registries, when stratified by race and compared to other locally advanced breast cancers, suggest that IBC has a disproportionately high incidence, prevalence & shorter median survival time in African Americans (AA) compared to Caucasian American (CA) patients. IBC health disparities that are independent of external factors like differences in income, screening rates, and access to health care suggest a biological component to poor outcomes. IBC pathobiology is also unique wherein instead of a solid tumor, tightly packed tumor cell clusters/emboli are formed with a propensity for lymphatic dissemination. The underlying mechanisms for this extremely aggressive breast cancer phenotype are largely unknown and, therefore, present a major impediment to identifying the molecular underpinnings for health disparities in IBC patients.

Methods and Results: In order to understand how IBC cells evade cell death signals in the host microenvironment, we conducted comparative analysis of the largest collection of untreated primary tumor samples of IBC (N=137), along with stage- and subtype-matched non-IBC (N=252) and normal breast tissue. Results reveal that pretreatment tumor tissue samples from IBC patients have a heightened expression of adaptive stress response genes comprised of high levels of the nuclear transcription factor, NFkappaB, and its target genes in the anti-apoptotic and immune/inflammatory pathways that correlate with cell survival. In addition, guided by analysis based on presence of tumor infiltrating leukocytes in IBC (N=69) and non-IBC (N=62) patient samples, we have identified a set of pathways and genes that have the ability to distinguish the immune responses in IBC and non-IBC patients in a subtype independent manner. In particular, interferon alpha/beta and NFκB signaling pathways were differentially regulated in IBC vs. non-IBC. Gene expression driven analysis of enrichment of leukocyte subsets reveal specific differences in plasma cells and effector memory CD8 cells in IBC bulk tumor samples. Preliminary data analysis of gene expression data sets from laser microdissected epithelium and stromal compartments of AA and CA breast cancer patients also show enrichment of plasma cells, effector memory CD4+, and M1 macrophages. Studies are ongoing to characterize these immune profiles that are unique and distinguishable in IBC patients and further identify race-related differences. Most importantly, we discovered that the constitutive NFκB hyperactivation observed in IBC tumor cells is driven by stress-mediated translational upregulation of the most potent anti-apoptotic protein, XIAP. Interestingly, XIAP:NFκB overexpressing cells are highly resistant to immunotherapy mediated cell death. These data strongly suggest that in IBC, host immune phenotype promotes outgrowth of cell death resistant population and specific tumor cell pro-survival signaling mechanisms that enhances invasion and lymphatic dissemination. We have developed novel in vitro IBC tumor emboli culture model and a transgenic mouse bearing red fluorescent lymphatic vasculature that allow recapitulating host factors to define tumor cell signaling mechanisms on immune effector function and the resultant invasive phenotype.

Conclusions: As the incidence is rising and targets for therapy are scant, IBC has the potential to become a major public health disparity concern. This study reveals that the immune factors in the host microenvironment may interact with underlying IBC genetics to promote the aggressive nature of the tumor, and more specifically, these factors may be one of the sources of biologic variation between patients of different ethnicities leading to IBC disparity outcomes. Supported in part by Duke IBC Consortium, DCI NIH CAO14236 development funds (GRD), DoD W81XWH-13-1-0047 (GRD).

Citation Format: Gayathri R. Devi, Eun-Sil Shelley Hwang, John Stewart, Michael A. Morse, Steven Van Laere. Immune pathway dysregulations in inflammatory breast cancer health disparity. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B44.