Role of cystine/glutamate transporter SLC7A11 in breast cancer brain metastatic cells.

Abstract

e13123 Background: Brain metastases in patients with triple-negative breast cancer (TNBC) pose many challenges due to their aggressive nature and limited treatment options. These tumors are able to grow and survive despite living in this unique low-lipid brain environment. To combat metabolic stress within the brain, breast cancer brain metastatic (BCBM) cells become more efficient at synthesizing fatty acids to use as their main energy source. These tumors rely on converting acetate to acetyl-CoA via acetyl-CoA synthetase 2 (ACSS2) in order to generate lipids. We have found that by targeting ACSS2, either genetically or pharmacologically, we can induce a form of cell death called ferroptosis in BCBM cells. Additionally, ACSS2 correlated to the regulation of the ferroptosis regulator protein SLC7A11. SLC7A11 is a cystine/glutamate transporter that protects cells from ferroptosis. We wanted to test the sensitivity of BCBM cells to the inhibition of SLC7A11. Methods: We stably knocked down SLC7A11 expression using RNAi in BCBM cells and confirmed the knockdown using Western blot. Soft agar assay was performed to assess the anchorage-independent cell growth of BCBM cells in vitro. Cell growth was also assessed in BCBM cells using an ex vivo model. Results: Soft agar assay showed that reducing SLC7A11 levels in BCBM cells blocks anchorage-independent cell growth in vitro . Additionally, targeting SLC7A11 in BCBM cells also blocks growth ex vivo . Conclusions: Thus, our data suggests that SLC7A11 may serve as a therapeutic target for treating BCBM tumors.