Abstract LB-296: Breast cancer metabolism in association with diabetes

Abstract

Abstract Diabetes and cancer are diseases that have a tremendous impact on health worldwide. Epidemiologic evidence suggests that people with diabetes are at an increased risk of various cancers including liver, pancreas and breast cancer. In line with this, we are finding that breast cancer patients who have diabetes (both type I and II) have decreased breast cancer-specific survival, indicating that diabetes may affect tumor biology and increase disease aggressiveness. To further investigate how diabetes promotes the progression of breast cancer, we performed global metabolic profiling and gene expression analysis of matched tumors from 18 diabetes and 18 non-diabetes breast cancer patients. Patient characteristics in each group included 12 estrogen receptor-positive (ER+) and 6 ER-negative tumors from 14 African American and 4 European American patients. We also performed immunohistochemistry of key disease-associated marker proteins in tumors of these patients. Results from the metabolomic analysis showed a significant accumulation of glycogen metabolic intermediates in breast tumors of diabetes patients, indicating changes in glycogen metabolism in tumor biology. Gene expression analysis showed differential expression of more numerous transcripts in the diabetic vs non-diabetic tumors. Interestingly, the top gene on this list was PPP1R3C, a gene involved in regulation of glycogen metabolism. We validated the higher expression of PPP1R3C in diabetic breast tumors by qRT-PCR and are currently performing an immunohistochemical evaluation of FFPE tumors. Other immunohistochemical staining of tumors from diabetic and non-diabetic patients showed significantly higher stromal expression of indolamine-2,3-dioxgenase (IDO) in breast tumors associated with diabetes, which indicates an immunosuppressive tumor microenvironment. To further corroborate our patient studies in cell culture systems, we began to use cytokine arrays in order to examine media of breast cancer cells treated with high glucose, which potentially mimics diabetes condition in cell culture. As a preliminary observation, we noticed a decrease in the level of certain cytokines in ER+ breast cancer cells (MCF7 and T47D). Notably, these cytokines remained unaltered in the conditioned media of non-neoplastic cells (MCF10A, MCF12A) grown under high glucose. Thus, under high glucose condition, ER+ breast cancer cells may secret a different cytokine repertoire, which would prevent recruiting immune cells into the tumor microenvironment and thereby may create an immunosuppressive tumor microenvironment. In conclusion, our current data indicate that diabetes may promote breast cancer progression by altering glycogen metabolism and by creating an immunosuppressive tumor microenvironment, which we currently further investigate. Citation Format: Gatikrushna Panigrahi, Tiffany H. Dorsey, Wei Tang, Stefan Ambs. Breast cancer metabolism in association with diabetes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-296.