Abstract A64: Immune and metabolic mechanisms regulate the microenvironment in triple-negative breast cancer

Abstract

Abstract African American (AA) women experience obesity and cancer risks that differ from white women. Obesity prevalence, risk of poor-prognosis triple-negative breast cancer (TNBC), and mortality rate are all higher among AA women. Obesity-driven Type 2 diabetes (T2D) is twice as common in AA women as white women in the U.S. and is associated with 20% increased risk of breast cancer. Differences by subtype are not well understood, yet recent evidence from our group supports a stronger association with ER- cancer. T2D is a systemic, chronic inflammatory disease, with local inflammation of breast adipose tissue that may promote metastasis of breast cancer. Yet about a quarter of AA adults with obesity remain relatively “metabolically healthy” despite obesity, with reduced cardiovascular and T2D risks and lower inflammation; emerging data suggest that this subgroup is also protected from breast cancer. Approach: Inflammation in nondiabetic adults with obesity is not well understood, and the few previous studies in this area only examined traditional markers like interleukin (IL)-6, TNF-α and C-reactive protein. We comprehensively profiled plasma cytokines to develop an unbiased signature of inflammation associated with obesity and T2D in a nonclinical population of AA women with obesity. Methods: Cytokines were profiled from 39 AA women with obesity who donated plasma to the Komen Tissue Bank, divided among women with T2D and matched nondiabetic controls. Multiplex bead arrays of analytes were used to quantify 88 cytokines and chemokines in association with clinical diagnoses of metabolic health. Regression models were generated after elimination of outliers. We functionally validated chemokines in human breast cancer models of migration, invasion, epithelial-to-mesenchymal transition (EMT), and cancer cell “stemness.” Results: Among women with obesity, T2D is associated with breast adipocyte hypertrophy and with six plasma analytes, including four chemokines, CCL2, CCL16, GRO-1, and CXCL16; and two growth factors, IL-2 and epidermal growth factor. In addition, three analytes are associated with obesity independently of T2D: IL-4, soluble CD40 ligand, and CCL3. Several of these factors are associated with aggressiveness of breast cancer in vitro. EMT phenotypes are critically controlled by the BET bromodomain proteins, including BRD2 and BRD4; invasion and migration in TNBC are controlled only by BRD4. These transcriptional coregulators can be inhibited by new small-molecule epigenetic drugs, suggesting a chemoprotective approach for AA women at risk for breast cancer metastasis. Conclusion and Implications: Risks for breast cancer incidence and progression are not distributed evenly, and are likely stratified by abnormal metabolism and its associated chronic inflammation. Yet the current standard of care in breast oncology does not fully consider the role of “immunometabolism” as a driver of metastasis. New noninvasive methods of cytokine and chemokine profiling might improve diagnosis and clinical decision making for underserved patients. Specific inflammatory cytokines and chemokines, which are likely to be critical effectors to drive advanced forms of breast cancer, must be validated in prospective observational studies. Note: This abstract was withdrawn and not presented at the conference. Citation Format: Guillaume Andrieu, Paola Sebastiani, Kimberly A. Bertrand, Julie R. Palmer, Gerald V. Denis. Immune and metabolic mechanisms regulate the microenvironment in triple-negative breast cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A64.