Abstract 3744: Differences in lipid metabolism between non-metastatic and metastatic breast cancer cells

Abstract Breast cancer remains a serious public health concern, as it accounts for 30% of estimated new cancer cases among US women this year. Importantly, metastasis is the primary contributor to breast cancer fatality; therefore, preventing the progression of breast cancer is crucial. One emerging hallmark of cancer is the dysregulation of cellular energetics. Specifically, there is an association between breast cancer aggressiveness and neutral lipid accumulation in cytoplasmic lipid droplets (CLDs). Although this relationship was first identified decades ago, large gaps still exist regarding how breast cancer cells accumulate excess lipids, and how those lipids may contribute to breast cancer metastasis. We hypothesize that the neutral lipids stored in CLDs in metastatic cells can be utilized for energy production to drive migration, a critical step of cancer metastasis. To test this hypothesis, we compared triacylglycerol levels (triacylglycerol assay), CLD accumulation (transmission electron microscopy), mRNA levels of genes involved in lipid metabolism (qPCR), and cell migration (wound healing assay) between non-metastatic MCF10A-ras and metastatic MCF10CA1a human breast cancer cells. Both cell models are derived from the same parental mammary epithelial cell line. Consistent with previous literature, the metastatic cells had significantly more triacylglycerol (110-fold) and CLDs than the non-metastatic cells. In addition, the metastatic cell line had significantly higher mRNA abundance of de novo lipogenic enzymes compared to the non-metastatic cells, including a 3-fold increase in ATP citrate lyase expression (p=0.02) and a 2-fold increase in fatty acid synthase expression (p=0.04), suggesting greater lipid synthetic capability in the metastatic cells. Interestingly, cell migration of the metastatic cell line was reduced by 43% 24 hours after scratch and treatment with etomoxir, an irreversible inhibitor of carnitine palmitate-transferase I (p = 0.005 compared to vehicle control). In contrast, etomoxir had no effect on the rate of migration of the non-metastatic cells compared to vehicle control. Since etomoxir reduces fatty acid oxidation capacity, the results suggest that lipids stored in metastatic cells provide substrate for energy production needed to promote breast cancer cell migration. These results support the hypothesis that accumulation of CLDs in metastatic cells, potentially due to upregulated de novo lipogenesis, drive the progression of breast cancer by providing substrate for fatty acid oxidation to support the key step of the metastatic cascade, migration. Citation Format: Chaylen Andolino, Josie Asher, Alyssa S. Zembroski, Kimberly Buhman, Dorothy Teegarden. Differences in lipid metabolism between non-metastatic and metastatic breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3744.