Targeting ferroptosis in breast cancer

Li, Zhaoqing; Cao, Feng; Chen, Cong; Zhou, Yulu; Hu, Dongyan; Yang, Jingjing; Chen, Yongxia; Zhuo, Wenying; Mao, Misha; Zhang, Xun; Xu, Ling; Wang, Linbo; Zhou, Jichun

doi:10.1186/s40364-020-00230-3

Cited by 124 publications

(73 citation statements)

References 315 publications

(375 reference statements)

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“…Ferroptosis is a novel form of regulated cell death characterized by destruction of intracellular redox balance and non-apoptosis [ 5 ]. Ferroptosis has become a promising therapeutic option for triggering cancer cell death [ 6 ]. It is reported that siramesine and lapatinib are effective ferroptosis inducers in breast cancer [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients

Wang

Wei

et al. 2021

BMC Cancer

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Background Breast cancer (BRCA) is a malignant tumor with high morbidity and mortality, which is a threat to women’s health worldwide. Ferroptosis is closely related to the occurrence and development of breast cancer. Here, we aimed to establish a ferroptosis-related prognostic gene signature for predicting patients’ survival. Methods Gene expression profile and corresponding clinical information of patients from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. The Least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis model was utilized to construct a multigene signature. The Kaplan-Meier (K-M) and Receiver Operating Characteristic (ROC) curves were plotted to validate the predictive effect of the prognostic signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway and single-sample gene set enrichment analysis (ssGSEA) were performed for patients between the high-risk and low-risk groups divided by the median value of risk score. Results We constructed a prognostic signature consisted of nine ferroptosis-related genes (ALOX15, CISD1, CS, GCLC, GPX4, SLC7A11, EMC2, G6PD and ACSF2). The Kaplan-Meier curves validated the fine predictive accuracy of the prognostic signature (p < 0.001). The area under the curve (AUC) of the ROC curves manifested that the ferroptosis-related signature had moderate predictive power. GO and KEGG functional analysis revealed that immune-related responses were largely enriched, and immune cells, including activated dendritic cells (aDCs), dendritic cells (DCs), T-helper 1 (Th1), were higher in high-risk groups (p < 0.001). Oppositely, type I IFN response and type II IFN response were lower in high-risk groups (p < 0.001). Conclusion Our study indicated that the ferroptosis-related prognostic signature gene could serve as a novel biomarker for predicting breast cancer patients’ prognosis. Furthermore, we found that immunotherapy might play a vital role in therapeutic schedule based on the level and difference of immune-related cells and pathways in different risk groups for breast cancer patients.

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Section: Introductionmentioning

confidence: 99%

Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients

Wang

Wei

et al. 2021

BMC Cancer

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“…While successful treatment paradigms have emerged for breast cancers expressing estrogen, progesterone, or Her2 receptors, triple negative breast cancers (TNBCs) that do not express any of these receptors are refractory to conventional chemotherapeutics and have a markedly poor prognosis [ 8 ]. Well-established chemical inducers of ferroptosis, such as the GPX4 inhibitor Rsl-3 and the xCT inhibitor Erastin, and their derivatives, are currently being explored as potential therapeutics for breast cancer therapy and have been shown to exert toxicity in these and other cancer cells [ 9 ]. On the other hand, what determines the sensitivity and resistance of cells to these compounds is a critical issue that must be further explored to develop ferroptotic induction as a valid therapeutic strategy for cancer.…”

Section: Introductionmentioning

confidence: 99%

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

et al. 2021

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Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal samples, and that this is tightly correlated with the increased expression of the xCT subunits SLC7A11 and SLC3A2. Erastin depletes levels of the antioxidant selenoproteins GPX4 and GPX1 in breast cancer cells by inhibiting xCT-dependent extracellular reduction which is required for selenium uptake and selenocysteine biosynthesis. Unexpectedly, while breast cancer cells are resistant compared to nontransformed cells against oxidative stress inducing drugs, at the same time they are hypersensitive to lipid peroxidation and ferroptosis induced by Erastin or Rsl-3, indicating that they are ‘addicted’ to the xCT/GPX4 axis. Our findings provide a strategic basis for targeting the anti-ferroptotic machinery of breast cancer cells depending on their xCT status, which can be further explored.

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“…Ferroptosis is a novel form of cell death related to iron-caused accumulation of lipid reactive oxygen species (ROS) ( Dixon et al, 2012 ). Accumulating studies have indicated that targeting ferroptosis may be a feasible strategy for therapy of breast cancer and ovarian cancer ( Li et al, 2020 ). It was proposed that triple negative breast cancer (TNBC) patients were more sensitive to ferroptosis than estrogen receptor ( Wang et al, 2021 )-positive patients, which provided a potential therapeutic strategy for TNBC patients ( Doll et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Lidocaine Promoted Ferroptosis by Targeting miR-382-5p /SLC7A11 Axis in Ovarian and Breast Cancer

Sun

Zhang

2021

Front. Pharmacol.

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Ovarian and breast cancer are prevalent female malignancies with increasing occurrence incidence and metastasis, significantly affecting the health and life quality of women globally. Anesthetic lidocaine has presented anti-tumor activities in the experimental conditions. However, the effect of lidocaine on ovarian and breast cancer remains elusive. We identified the important function of lidocaine in enhancing ferroptosis and repressing progression of ovarian and breast cancer. Our data showed that lidocaine further repressed erastin-inhibited ovarian and breast cancer cell viabilities. The treatment of lidocaine induced accumulation of Fe2+, iron and lipid reactive oxygen species (ROS) in ovarian and breast cancer cells. The ovarian and breast cancer cell proliferation was suppressed while cell apoptosis was induced by lidocaine in vitro. Lidocaine attenuated invasion and migration of ovarian and breast cancer cells as well. Regarding the mechanism, we found that lidocaine downregulated solute carrier family 7 member 11 (SLC7A11) expression by enhancing microRNA-382-5p (miR-382-5p) in the cells. The inhibition of miR-382-5p blocked lidocaine-induced ferroptosis of ovarian and breast cancer cells. MiR-382-5p/SLC7A11 axis was involved in lidocaine-mediated inhibition of ovarian and breast cancer cell proliferation in vitro. The miR-382-5p expression was down-regulated but SLC7A11 expression was up-regulated in clinical ovarian and breast cancer samples. Furthermore, the treatment of lidocaine repressed tumor growth of ovarian cancer cells in vivo, in which the miR-382-5p expression was increased while SLC7A11 expression was decreased. Consequently, we concluded that the lidocaine promoted ferroptosis by miR-382-5p/SLC7A11 axis in ovarian and breast cancer cells. The clinical value of lidocaine in the treatment of ovarian and breast cancer deserves to be proved in detail.

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Targeting ferroptosis in breast cancer

Cited by 124 publications

References 315 publications

Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients

Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients

xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers

Lidocaine Promoted Ferroptosis by Targeting miR-382-5p /SLC7A11 Axis in Ovarian and Breast Cancer

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