The role of SLC7A11 in regulating breast cancer brain metastasis

Abstract

Brain metastasis in breast cancer patients represents an advanced and often fatal stage of disease, with survival typically less than one year following diagnosis. Despite therapeutic progress in primary tumors, effective treatments for breast cancer brain metastasis (BCBM) remain limited, highlighting the need for new mechanistic insights and therapeutic strategies. Our lab has recently found that SLC7A11 levels are significantly enriched in BCBM patient samples and are required for BCBM growth in vivo. SLC7A11, is a cystine/glutamate antiporter and is critical for glutathione (GSH) synthesis and protection against ferroptosis, a form of iron-dependent cell death. While it's function in ferroptosis resistance is well established, it's broader role in BCBM progression remains incompletely defined. Proteomic analyses of breast cancer cells overexpressing SLC7A11 revealed upregulation of extracellular matrix (ECM) and integrin-associated proteins, prompting investigation into regulation of ECM signaling pathways. In this study, we demonstrate that SLC7A11 overexpression significantly increases integrin [alpha]3, [alpha]6, and [beta]1 protein levels and focal adhesion kinase (FAK) activity, as evidenced by increased phosphorylation at tyrosine 397. Consistent with this data, using clonogenic survival assays, SLC7A11 overexpressing breast cancer cells showed resistance to FAK inhibitor induced cell death. In order to evaluate therapeutic potential of FAK inhibitors, we utilized an ex vivo brain slice model of BCBM. Treatment with clinically relevant FAK inhibitors including, PND-1186 and Defactinib resulted in significant tumor regression compared to controls. These findings indicate that FAK signaling contributes to BCBM tumor maintenance and that it's inhibition can effectively suppress tumor growth. Collectively, our results identify SLC7A11 as a non-canonical regulator of ECM/integrin-mediated FAK survival signaling in brain metastatic breast cancer cells. Targeting this axis may represent a promising strategy to enhance therapeutic vulnerability and improve outcomes in patients with breast cancer brain metastasis.