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BMC Cancer

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Open Access 01-12-2021 | Breast Cancer | Research

Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer

Authors: Wenqing Tang, Fangshi Xu, Meng Zhao, Shuqun Zhang

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Ferroptosis, a new form of programmed cell death, has great potential for cancer treatment. However, the roles of ferroptosis-related (FR) genes in breast cancer (BC) remain elusive.

Materials and methods

Using TCGA database, a novel FR risk signature was constructed through the Lasso regression analysis. Meanwhile, its prognostic value was assessed by a series of survival analyses. Besides, a nomogram was constructed to predict the overall survival rate (OSR) of individual at 1,3,5 year. Four validation cohorts (n = 2248), including METABRIC, GSE58812, GSE20685 and ICGC-KR datasets, were employed to test the prognostic value of FR risk signature. The effects of FR risk signature on BC immune microenvironment were explored by CIBERSORT algorithm and ssGSEA method. The histological expressions of FR risk genes were presented by HPA database. The biofunctions of SQLE were determined by qPCR, MTT, wound-healing and Transwell assays.

Results

We constructed a novel FR risk signature consisting of eight genes. High FR risk led a poor prognosis and was identified as an independent prognostic factor. Besides, A higher proportion of patients with luminal A type was observed in low-risk group (53%), while a higher proportion of patients with basal type in high-risk group (24%). FR risk score could discriminate the prognostic difference of most clinical subgroups, except for M1 stage, HER2 and basal types. Moreover, its prognostic value was successfully validated in other four cohorts. Through immune analyses, we found that the reduced infiltration levels of CD8+ and NK cells, whereas the enhanced activity of antigen presentation process appeared in high FR risk. Then, FR risk score was found to weakly correlate with the expressions of six immune checkpoints. Through the experiments in vitro, we confirmed that overexpression of SQLE could promote, whereas blocking SQLE could inhibit the proliferative, migrative and invasive abilities of BC cells.

Conclusions

FR risk signature was conducive to BC prognostic assessment. High FR risk level was closely associated with BC immunosuppression, but may not predict ICIs efficacy. Moreover, SQLE was identified as a crucial cancer-promoting gene in BC. Our findings provide new insights into prognostic assessment and molecular mechanism of BC.

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Ahmad A. Breast Cancer statistics: recent trends. Adv Exp Med Biol. 2019;1152:1–7. https://doi.org/10.1007/978-3-030-20301-6_1.CrossRefPubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.CrossRefPubMed

Pfeiffer RM, Webb-Vargas Y, Wheeler W, Gail MH. Proportion of U.S. trends in breast Cancer incidence attributable to long-term changes in risk factor distributions. Cancer Epidemiol Biomark Prev. 2018;27(10):1214–22. https://doi.org/10.1158/1055-9965.EPI-18-0098.CrossRef

Chen Z, Xu L, Shi W, Zeng F, Zhuo R, Hao X, et al. Trends of female and male breast cancer incidence at the global, regional, and national levels, 1990-2017. Breast Cancer Res Treat. 2020;180(2):481–90. https://doi.org/10.1007/s10549-020-05561-1.CrossRefPubMed

Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, et al. European cancer mortality predictions for the year 2019 with focus on breast cancer. Ann Oncol. 2019;30(5):781–7. https://doi.org/10.1093/annonc/mdz051.CrossRefPubMed

Wang H, Liu C, Zhao Y, Gao G. Mitochondria regulation in ferroptosis. Eur J Cell Biol. 2020;99(1):151058. https://doi.org/10.1016/j.ejcb.2019.151058.CrossRefPubMed

Hassannia B, Vandenabeele P, Vanden BT. Targeting Ferroptosis to Iron out Cancer. Cancer Cell. 2019;35(6):830–49. https://doi.org/10.1016/j.ccell.2019.04.002.CrossRefPubMed

Xu G, Wang H, Li X, Huang R, Luo L. Recent progress on targeting ferroptosis for cancer therapy. Biochem Pharmacol. 2021;190:114584. https://doi.org/10.1016/j.bcp.2021.114584.

Mou Y, Wu J, Zhang Y, Abdihamid O, Duan C, Li B. Low expression of ferritinophagy-related NCOA4 gene in relation to unfavorable outcome and defective immune cells infiltration in clear cell renal carcinoma. BMC Cancer. 2021;21(1):18. https://doi.org/10.1186/s12885-020-07726-z.CrossRefPubMedPubMedCentral

10.

Li H, Li L, Xue C, Huang R, Hu A, An X, et al. A Novel Ferroptosis-Related Gene Signature Predicts Overall Survival of Breast Cancer Patients. Biology (Basel). 2021;10(2):151. https://doi.org/10.3390/biology10020151.

11.

Wang D, Wei G, Ma J, Cheng S, Jia L, Song X, et al. Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients. BMC Cancer. 2021;21(1):645. https://doi.org/10.1186/s12885-021-08341-2.CrossRefPubMedPubMedCentral

12.

Wu ZH, Tang Y, Yu H, Li HD. The role of ferroptosis in breast cancer patients: a comprehensive analysis. Cell Death Discov. 2021;7(1):93. https://doi.org/10.1038/s41420-021-00473-5.CrossRefPubMedPubMedCentral

13.

Zhu L, Tian Q, Jiang S, Gao H, Yu S, Zhou Y, et al. A novel Ferroptosis-related gene signature for overall survival prediction in patients with breast Cancer. Front Cell Dev Biol. 2021;9:670184. https://doi.org/10.3389/fcell.2021.670184.CrossRefPubMedPubMedCentral

14.

Jézéquel P, Loussouarn D, Guérin-Charbonnel C, Campion L, Vanier A, Gouraud W, et al. Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response. Breast Cancer Res. 2015;17(1):43. https://doi.org/10.1186/s13058-015-0550-y.CrossRefPubMedPubMedCentral

15.

Kao KJ, Chang KM, Hsu HC, Huang AT. Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization. BMC Cancer. 2011;11(1):143. https://doi.org/10.1186/1471-2407-11-143.CrossRefPubMedPubMedCentral

16.

Zhou N, Bao J. FerrDb: a manually curated resource for regulators and markers of ferroptosis and ferroptosisdisease associations. Database (Oxford). 2020;2020:baaa021. https://doi.org/10.1093/database/baaa021.

17.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. https://doi.org/10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral

18.

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. https://doi.org/10.1016/j.cell.2012.03.042.CrossRefPubMedPubMedCentral

19.

Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31(2):107–25. https://doi.org/10.1038/s41422-020-00441-1.CrossRefPubMed

20.

Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73(11–12):2195–209. https://doi.org/10.1007/s00018-016-2194-1.CrossRefPubMedPubMedCentral

21.

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–79. https://doi.org/10.1038/cdd.2015.158.CrossRefPubMedPubMedCentral

22.

Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 2019;23(8):4900–12. https://doi.org/10.1111/jcmm.14511.CrossRefPubMedPubMedCentral

23.

Liu Z, Zhao Q, Zuo ZX, Yuan SQ, Yu K, Zhang Q, et al. Systematic Analysis of the Aberrances and Functional Implications of Ferroptosis in Cancer. iScience. 2020;23(7):101302.CrossRefPubMedPubMedCentral

24.

Wu G, Wang Q, Xu Y, Li Q, Cheng L. A new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. Aging (Albany NY). 2020;12(14):14933–48. https://doi.org/10.18632/aging.103553.CrossRef

25.

Budczies J, Klauschen F, Sinn BV, Győrffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS One. 2012;7(12):e51862. https://doi.org/10.1371/journal.pone.0051862.CrossRefPubMedPubMedCentral

26.

Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol Biol. 1711;2018:243–59. https://doi.org/10.1007/978-1-4939-7493-1_12.CrossRef

27.

Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinforma. 2013;14(1):7. https://doi.org/10.1186/1471-2105-14-7.CrossRef

28.

Uhlén M, Fagerberg L, Hallström B, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science (New York, NY). 2015;347(6220):1260419.CrossRef

29.

Lindskog C. The potential clinical impact of the tissue-based map of the human proteome. Expert Rev Proteomics. 2015;12(3):213–5. https://doi.org/10.1586/14789450.2015.1040771.CrossRefPubMed

30.

Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3(3):285–96. https://doi.org/10.1016/S1535-6108(03)00050-3.CrossRefPubMed

31.

Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A. 2016;113(34):E4966–75. https://doi.org/10.1073/pnas.1603244113.CrossRefPubMedPubMedCentral

32.

Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10(7):1604–9. https://doi.org/10.1021/acschembio.5b00245.CrossRefPubMedPubMedCentral

33.

Graham RM, Chua AC, Herbison CE, Olynyk JK, Trinder D. Liver iron transport. World J Gastroenterol. 2007;13(35):4725–36. https://doi.org/10.3748/wjg.v13.i35.4725.CrossRefPubMedPubMedCentral

34.

Montalbetti N, Simonin A, Kovacs G, Hediger MA. Mammalian iron transporters: families SLC11 and SLC40. Mol Asp Med. 2013;34(2–3):270–87. https://doi.org/10.1016/j.mam.2013.01.002.CrossRef

35.

Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12(8):1425–8. https://doi.org/10.1080/15548627.2016.1187366.CrossRefPubMedPubMedCentral

36.

Henning AN, Roychoudhuri R, Restifo NP. Epigenetic control of CD8(+) T cell differentiation. Nat Rev Immunol. 2018;18(5):340–56. https://doi.org/10.1038/nri.2017.146.CrossRefPubMedPubMedCentral

37.

MacLeod MK, Kappler JW, Marrack P. Memory CD4 T cells: generation, reactivation and re-assignment. Immunology. 2010;130(1):10–5. https://doi.org/10.1111/j.1365-2567.2010.03260.x.CrossRefPubMedPubMedCentral

38.

Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016;16(1):7–19. https://doi.org/10.1038/nrc.2015.5.CrossRefPubMed

39.

Cui CY, Ferrucci L. Macrophages in skeletal muscle aging. Aging (Albany NY). 2020;12(1):3–4. https://doi.org/10.18632/aging.102740.CrossRef

40.

Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol. 2019;106(2):345–58. https://doi.org/10.1002/JLB.3RU1018-378RR.CrossRefPubMed

41.

Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunity. Int Immunol. 2016;28(8):401–9. https://doi.org/10.1093/intimm/dxw025.CrossRefPubMedPubMedCentral

42.

Paolino G, Corsetti P, Moliterni E, Corsetti S, Didona D, Albanesi M, et al. Mast cells and cancer. G Ital Dermatol Venereol. 2019;154(6):650–68. https://doi.org/10.23736/S0392-0488.17.05818-7.CrossRefPubMed

43.

Liu T, Xia Q, Zhang H, Wang Z, Yang W, Gu X, et al. CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients. Aging (Albany NY). 2020;12(21):21809–36. https://doi.org/10.18632/aging.103999.CrossRef

44.

Wouters MCA, Nelson BH. Prognostic significance of tumor-infiltrating B cells and plasma cells in human Cancer. Clin Cancer Res. 2018;24(24):6125–35. https://doi.org/10.1158/1078-0432.CCR-18-1481.CrossRefPubMed

45.

Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24. https://doi.org/10.1038/s41577-019-0210-z.CrossRefPubMed

46.

Lin B, Du L, Li H, Zhu X, Cui L, Li X. Tumor-infiltrating lymphocytes: warriors fight against tumors powerfully. Biomed Pharmacother. 2020;132:110873. https://doi.org/10.1016/j.biopha.2020.110873.CrossRefPubMed

47.

Zhao X, Liu J, Ge S, Chen C, Li S, Wu X, et al. Saikosaponin a inhibits breast Cancer by regulating Th1/Th2 balance. Front Pharmacol. 2019;10:624. https://doi.org/10.3389/fphar.2019.00624.CrossRefPubMedPubMedCentral

48.

Zhou Y, Zhang Y, Guo G, Cai X, Yu H, Cai Y, et al. Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy-free, first-line treatment for PD-L1-positive non-small cell lung cancer. Clin Transl Med. 2020;10(1):107–15. https://doi.org/10.1002/ctm2.14.CrossRefPubMedPubMedCentral

49.

Xu H, Zhou S, Tang Q, Xia H, Bi F. Cholesterol metabolism: new functions and therapeutic approaches in cancer. Biochim Biophys Acta Rev Cancer. 1874;2020(1):188394. https://doi.org/10.1016/j.bbcan.2020.188394.CrossRef

50.

Brown AJ, Chua NK, Yan N. The shape of human squalene epoxidase expands the arsenal against cancer. Nat Commun. 2019;10(1):888. https://doi.org/10.1038/s41467-019-08866-y.CrossRefPubMedPubMedCentral

51.

Liang JY, Wang DS, Lin HC, Chen XX, Yang H, Zheng Y, et al. A novel Ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. Int J Biol Sci. 2020;16(13):2430–41. https://doi.org/10.7150/ijbs.45050.CrossRefPubMedPubMedCentral

52.

Hortobagyi GN, Edge SB, Giuliano A. New and important changes in the TNM staging system for breast Cancer. Am Soc Clin Oncol Educ Book. 2018;38:457–67. https://doi.org/10.1200/EDBK_201313.CrossRefPubMed

53.

Sporikova Z, Koudelakova V, Trojanec R, Hajduch M. Genetic markers in triple-negative breast cancer. Clin Breast Cancer. 2018;18(5):e841–50. https://doi.org/10.1016/j.clbc.2018.07.023.CrossRefPubMed

54.

Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271–7. https://doi.org/10.1200/JCO.2009.25.9820.CrossRefPubMed

55.

Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast. 2015;24(Suppl 2):S26–35. https://doi.org/10.1016/j.breast.2015.07.008.CrossRefPubMed

56.

Shen L, Zhou Y, He H, Chen W, Lenahan C, Li X, et al. Crosstalk between macrophages, T cells, and Iron metabolism in tumor microenvironment. Oxidative Med Cell Longev. 2021;2021:8865791–14. https://doi.org/10.1155/2021/8865791.CrossRef

57.

Dadkhah E, Naseh H, Farshchian M, Memar B, Sankian M, Bagheri R, et al. A cancer-array approach elucidates the immune escape mechanism and defects in the DNA repair system in esophageal squamous cell carcinoma. Arch Iran Med. 2013;16(8):463–70.PubMed

58.

Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):405–11. https://doi.org/10.1093/annonc/mdy518.CrossRefPubMed

59.

Zhang HY, Li HM, Yu Z, Yu XY, Guo K. Expression and significance of squalene epoxidase in squamous lung cancerous tissues and pericarcinoma tissues. Thorac Cancer. 2014;5(4):275–80. https://doi.org/10.1111/1759-7714.12087.CrossRefPubMedPubMedCentral

60.

Qin Y, Zhang Y, Tang Q, Jin L, Chen Y. SQLE induces epithelial-to-mesenchymal transition by regulating of miR-133b in esophageal squamous cell carcinoma. Acta Biochim Biophys Sin Shanghai. 2017;49(2):138–48. https://doi.org/10.1093/abbs/gmw127.CrossRefPubMed

61.

Stopsack KH, Gerke TA, Sinnott JA, Penney KL, Tyekucheva S, Sesso HD, et al. Cholesterol metabolism and prostate Cancer lethality. Cancer Res. 2016;76(16):4785–90. https://doi.org/10.1158/0008-5472.CAN-16-0903.CrossRefPubMedPubMedCentral

62.

Jiang P, Yang F, Zou C, Bao T, Wu M, Yang D, et al. The construction and analysis of a ferroptosis-related gene prognostic signature for pancreatic cancer. Aging. 2021;13(7):10396–414. https://doi.org/10.18632/aging.202801.CrossRefPubMedPubMedCentral

63.

Xu F, Zhang Z, Zhao Y, Zhou Y, Pei H, Bai L. Bioinformatic mining and validation of the effects of ferroptosis regulators on the prognosis and progression of pancreatic adenocarcinoma. Gene. 2021;795:145804. https://doi.org/10.1016/j.gene.2021.145804.CrossRefPubMed

Title: Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer
Authors: Wenqing Tang
Fangshi Xu
Meng Zhao
Shuqun Zhang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Checkpoint Inhibitors
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08892-4

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