The
cystine transporter (system xC-) is an
antiporter of
cystine and
glutamate. It has relatively low basal expression in most tissues and becomes upregulated in cells under oxidative stress (OS) as one of the genes expressed in response to the antioxidant response element promoter. We have developed 18F-5-fluoroaminosuberic
acid (FASu), a PET tracer that targets system xC- The goal of this study was to evaluate
18F-FASu as a specific gauge for system xC- activity in vivo and its potential for
breast cancer imaging. Methods:18F-FASu specificity toward system xC- was studied by cell inhibition assay, cellular uptake after OS induction with
diethyl maleate, with and without anti-xCT
small interfering RNA knockdown, in vitro uptake studies, and in vivo uptake in a system xC--transduced xenograft model. In addition, radiotracer uptake was evaluated in 3
breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1. Results:
Reactive oxygen species-inducing
diethyl maleate increased
glutathione levels and
18F-FASu uptake, whereas gene knockdown with anti-xCT
small interfering RNA led to decreased tracer uptake.
18F-FASu uptake was robustly inhibited by system xC- inhibitors or substrates, whereas uptake was significantly higher in transduced cells and
tumors expressing xCT than in wild-type HEK293T cells and
tumors (P < 0.0001 for cells, P = 0.0086 for
tumors).
18F-FASu demonstrated
tumor uptake in all 3
breast cancer cell lines studied. Among them,
triple-negative breast cancer MDA-MB-231, which has the highest xCT
messenger RNA level, had the highest tracer uptake (P = 0.0058 when compared with MCF-7; P < 0.0001 when compared with ZR-75-1). Conclusion:18F-FASu as a system xC- substrate is a specific PET tracer for functional monitoring of system xC- and OS imaging. By enabling noninvasive analysis of xC- responses in vivo, this
biomarker may serve as a valuable target for the diagnosis and treatment monitoring of certain breast
cancers.