PROJECT SUMMARY/ABSTRACT Diabetes increases the risk of breast cancer (BC) in women and mortality in patients with cancer. African- American (AA) women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from BC. In addition, many women gain weight after BC treatment and end up with diabetes. AA and Hispanic/Latina women are even more affected by this. There exist some important distinctions between the BC patients with and without diabetes in the regimen selection and outcomes of cancer therapy. Currently there are no specific treatments to target diabetes-associated BC. Our long-term goals are to understand the fundamental mechanisms of diabetes-induced BC progression, and to develop personalized treatments for diabetes-associated BC. Based on the metabolic differences between normal and cancer cells, we for the first time propose this safe and effective therapeutic strategy targeting cancer metabolism to “poison” BC cells, with relatively non-toxicity to normal cells. The present project focuses on targeting lactate metabolism and transport to induce BC cell death. The central hypothesis of this strategy is that pharmaceutical induction of glucose import and glycolysis to even higher levels while blocking the products of glycolysis from entering the tricarboxylic acid (TCA) cycle, results in production of high amounts of lactate. Meanwhile, blocking the export of excessive lactate by inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis and acidification within the cancer cells, causing their death. Our preliminary in vitro results indicate that this metabolic reprogramming strategy (MRS) can successfully block cancer cells proliferation. Moreover, we have identified CB-2 as a novel small molecule MCT4 inhibitor (Patent Application Number: 62/662,637). CB-2 has shown a significantly inhibitory effect on lactate secretion and striking cytotoxic activity against triple-negative breast cancer (TNBC) cells, which have a high glycolytic rate/MCT4 expression. Guided by strong preliminary data, we propose to pursue three Specific Aims to test this hypothesis: (1) To investigate the effect of MRS on energy metabolic pathways of different BC cell lines and the possible reasons for sensitivity or resistance to this approach. (2) To confirm the mechanism of action and anticancer activity of CB-2. (3) To test the effectiveness, safety, and potential side effects of this MRS in diabetic mouse models bearing human BC xenografts. Collectively, these studies will allow us to gain a more in-depth understanding of cancer cell metabolism and may in the long term reveal an effective therapeutic strategy for diabetes-associated BC and TNBCs. The complex biology that contributes to the unequal cancer burdens needs to be investigated to increase our basic understanding of cancer health disparities. Hence, investigating glucose metabolism features in tumor cells would be a significant step in shedding light on this health disparity. Moreover, searching new drug targets and developing new treatment methods in diabetes-associated BC contribute to decreasing cancer health disparities.

PROJECT NARRATIVE Diabetes mellitus may dramatically increase risk of breast cancer (BC) and mortality in patients with cancer. Our proposed studies aim to understand the fundamental mechanisms of diabetes-induced BC progression, and to develop personalized treatments for diabetes-associated BC. This research will allow us to gain a more in- depth understanding of cancer cell metabolism and reveal an effective therapeutic strategy for diabetes- associated BC and triple-negative breast cancer (TNBC), which may contribute to reducing cancer health disparities.