2022 Annual Meeting
Investigating the Impact of Metabolic Responses to Radiation Therapy on Triple Negative Breast Cancer Recurrence
Previous studies have shown that radiation therapy, a common treatment modality for triple-negative breast cancer (TNBC), has an impact on tumor cell recruitment and recurrence. With an almost 25% locoregional or distant recurrence rate, the altered metabolic profile of TNBC can be attributed to the metabolic responses within the breast cancer microenvironment. Additionally, TNBC has been seen to disproportionately affect obese patients, who experience a 20% higher risk of developing TNBC and lower overall survival rates. We hypothesized that the metabolic responses of irradiated fibroblasts in the breast cancer tissue can influence the recurrence rate of TNBC by creating a pro-tumorigenic environment. In this experiment, murine 3T3 fibroblasts were exposed to a 10 Gy dose of ionizing radiation and studied for 7 days post-IR. We were able to assess the response to radiation on cell growth using immunofluorescence staining with a Ki67 marker. Irradiated fibroblasts exhibited reduced cell proliferation over a 7-day period. Our previous work demonstrated irradiated fibroblasts increased lipid droplets. We hypothesized that this was due to increased fatty acid uptake. Using bodipy-labeled extracellular palmitate, irradiated fibroblasts demonstrated an increase in fatty acid accumulation over a 7-day period. This increase in fatty acid uptake correlated with increased lactate secretion by irradiated fibroblasts. 4T1 TNBC cells were grown to confluence in a culture insert 2-well dish, which introduced a gap between the cells. Cells were treated with irradiated fibroblast conditioned media (CM) with AZD3965 drug, an MCT 1/2 transporter inhibitor, or DMSO as control. Irradiated CM treatment increased TNBC cell migration. Additionally, the inhibition of the MCT 1/2 transporter via the AZD3965 drug inhibited lactate uptake, which decreased TNBC cell migration. These results elucidate a potential mechanism between fibroblast and cancer cells that can promote a pro-tumorigenic environment and facilitate recurrence.