| Objective: Triple-negative breast cancer,commonly known as TNBC,has the highest mortality rate of all breast cancers.It is also the type of breast cancer that is most likely to return,and it is resistant to chemotherapeutic drugs that target apoptosis.The advancements that have been made in the research of ferroptosis in TNBC are mostly reflected in chemotherapy resistance and targeted therapy.This is the case at the molecular level.Recent research has demonstrated that ferroptosis can influence the growth of tumor cells and angiogenesis,which can ultimately lead to the development of tumors.As a result,ferroptosis is considered to play an essential part in the therapy of malignancies and has garnered a lot of interest as a result.The clinical applicability of iron death in TNBC,on the other hand,has not been thoroughly examined.Methods: For the purpose of this investigation,the primary study data were obtained by downloading them from the Cancer Genome Atlas Data(TCGA)and the Genomics Database for Drug Sensitivity in Cancer(GDSC).We were able to retrieve gene expression data and clinical data pertaining to TNBC patients from the TCGA database.The clinical data included information on patients with TNBC regarding their survival status,gender,pathological grade,stage of tumor lymph node metastasis(TNM),and the amount of time they had survived.The rank sum test was utilized in this investigation in order to determine the level of expression of ferroptosis-related genes(FRGs)in TNBC.The effect of FRGs on the predicted overall survival time in TNBC was evaluated using a Kaplan-Meier curve and a Log-rank test,respectively.The FRGs that had the most significant influence on the prognosis of TNBC patients were screened by using the lasso algorithm(LASSO)regression analysis combined with the proportional risk regression model.Additionally,the overall survival(OS)of TNBC patients was evaluated by constructing a line graph based on CDGSH iron-sulfur domain protein 1(CISD1)and clinical information.Scatter plots relating to drug sensitivity for TNBC were downloaded from the GDSC database,and associated data were also retrieved.This allowed for the search for medications that were sensitive to individuals with high CISD1 expression.In order to provide additional confirmation of the drug sensitivity results,molecular docking techniques were utilized.For the purpose of determining whether or not immunotherapy is feasible,the Spearman correlation of tumor immune infiltration as well as other markers were utilized.Results: 1.In FRGs,cyclin-dependent kinase inhibitor 1A(CDKN1A),cardiolipin synthase 2(CLS2),reticulocyte-derived 2-like protein 2(NFE2L2),glutathione peroxidase 4(GPX4),dipeptidyl peptidase 4(DPP4),farnesyl diphosphate farnesyltransferase 1(FDFT1),nuclear receptor coactivator 4(NCOA4),citrate synthase(CS),arachidonic acid-15-lipoxygenase(ALOX15),lysolecithin acyltransferase 3(LPCAT3),acyl coenzyme A synthase long chain family member 4(ACSL4)and atlastin GTPase 1(ATL1)were less expressed in TNBC than in normal tissues.Heat shock protein A5(HSPA5),endoplasmic reticulum membrane(EMC2),solute carrier family 7 member11(SLC7A11),metallothionein 1G(MT1G),Fanconi anemia complementation group D2(FANCD2),CISD1,spermidine/spermine N1-acetyltransferase 1(SAT1),transferrin receptor(TFRC),ribosomal protein L8(RPL8),cysteinyl t RNA synthase(CARS1)and ATP synthase membrane subunit C site 3(ATP5MC3)were expressed higher in TNBC than in normal tissues.2.Using Kaplan-Meier curves and Log-rank tests,we found that both SLC1A5(P=0.026,HR=2.61)and CISD1(P=0.012,HR=1.07)had a significant effect on the prognosis of TNBC.3.LASSO regression analysis provided additional confirmation that both CISD1 and SLC1A5 were oncogenes for TNBC.Patients with TNBC were given a risk score,and this information was used to place them in one of two groups.Patients with TNBC with a high risk score had a shorter OS compared to those with a low risk score.(median survival time=11.7,P=0.05).4.The predicted column line graph for overall survival at 1,3,and 5 years for TNBC patients demonstrated that CISD1,ethnicity,and N stage were connected to the prognosis of overall survival(P=0.001,consistency index(C-index): 0.818).5.The findings of this investigation indicated a negative trend of connection between the expression of CISD1 and the total number of B cells(P=6.79e-06),CD4+ T cells(P=0.001),and CD8+ T cells(P=0.018).These findings were based on the findings of the TIMER database.According to the results of the TCGA-TNBC study,patients with TNBC who had high levels of CISD1 expression had significantly lower TIDE scores than patients with TNBC who had low levels of CISD1 expression(Wilcoxon rank sum test,P=0.002)Patients with TNBC who fall into the CISD1 high expression group are encouraged to consider immunotherapy.6.Patients with TNBC who had high levels of CISD1 expression were found to have a greater sensitivity to vincristine when the results of an analysis using the relevant data from the GDSC database were combined with molecular docking.Conclusion: When it comes to FRGs,the expression of CISD1 is the most crucial factor for overall survival in TNBC.The prognosis of patients with TNBC is impacted by a variety of characteristics,including CISD1,ethnicity,and N stage.There is a possibility that immunotherapy plus vincristine will be effective for treating TNBC patients who fall into the high CISD1 expression category. |
