Breast cancer is a prevalent malignancy worldwide.The majority of breast cancers belong to the estrogen receptor(ER)-positive luminal subtype that can be effectively treated with antiestrogen therapies.However,a signi...Breast cancer is a prevalent malignancy worldwide.The majority of breast cancers belong to the estrogen receptor(ER)-positive luminal subtype that can be effectively treated with antiestrogen therapies.However,a significant portion of such malignancies become hormone-refractory and incurable.Cancer cells often uptake more cystines to increase glutathione(GSH)biosynthesis and reduce reactive oxygen species(ROS),thereby preventing ROS-induced ferroptosis and leading to therapeutic resistance.However,few molecules of these processes are targetable for cancer therapy.However,few therapeutic targets have been established that target these processes.Here,we report that the gene for SLC7A13,a member of the SLC7A13-SLC3A1 cystine transporter,was amplified and overexpressed in 19.7% and 49.7% of breast cancers,respectively.SLC7A13 amplifi cation and overexpression were associated with worse overall survival and disease-free survival in patients with luminal breast cancer.Functionally,SLC7A13 overexpression promoted,while its silencing attenuated,cell survival or proliferation.Molecularly,SLC7A13 silencing reduced cystine uptake and GSH biosynthesis,leading to increased lipid ROS levels.The cryo-EM structure of the human SLC7A13-SLC3A1 complex was determined at 2.64AA,revealing a dimer-of-heterodimers architecture similar to that of other SLC3A1-linked transporters.A specific substrate-binding pocket was identified,containing distinct residues,which suggests a regulatory role in the cystine transporter.These findings suggest that the SLC7A13-SLC3A1 cystine transporter is a therapeutic target for treating luminal breast cancer.They also provide the structural insights for therapeutic development targeting the cystine transporter.展开更多
基金supported by the National Natural Science Foundation of China 32371267 and 32422039(R.Y.)Science,Technology and Innovation Commission of Shenzhen Municipality JCYJ20200109141229255(J.T.D.)+2 种基金Science,Technology and Innovation Commission of Shenzhen Municipality 20200925174802001(.T.D.)Natural Science Foundation of Guangdong Province 2024A1515011288(R.Y.)Major Talent Recruitment Program of Guangdong Province 2021QNO2Y167(R.Y.).
文摘Breast cancer is a prevalent malignancy worldwide.The majority of breast cancers belong to the estrogen receptor(ER)-positive luminal subtype that can be effectively treated with antiestrogen therapies.However,a significant portion of such malignancies become hormone-refractory and incurable.Cancer cells often uptake more cystines to increase glutathione(GSH)biosynthesis and reduce reactive oxygen species(ROS),thereby preventing ROS-induced ferroptosis and leading to therapeutic resistance.However,few molecules of these processes are targetable for cancer therapy.However,few therapeutic targets have been established that target these processes.Here,we report that the gene for SLC7A13,a member of the SLC7A13-SLC3A1 cystine transporter,was amplified and overexpressed in 19.7% and 49.7% of breast cancers,respectively.SLC7A13 amplifi cation and overexpression were associated with worse overall survival and disease-free survival in patients with luminal breast cancer.Functionally,SLC7A13 overexpression promoted,while its silencing attenuated,cell survival or proliferation.Molecularly,SLC7A13 silencing reduced cystine uptake and GSH biosynthesis,leading to increased lipid ROS levels.The cryo-EM structure of the human SLC7A13-SLC3A1 complex was determined at 2.64AA,revealing a dimer-of-heterodimers architecture similar to that of other SLC3A1-linked transporters.A specific substrate-binding pocket was identified,containing distinct residues,which suggests a regulatory role in the cystine transporter.These findings suggest that the SLC7A13-SLC3A1 cystine transporter is a therapeutic target for treating luminal breast cancer.They also provide the structural insights for therapeutic development targeting the cystine transporter.
