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Expression of genes related to iron homeostasis in breast cancer

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Abstract

Background

The dysfunctions in the metabolism of iron have an important role in many pathological conditions, ranging from disease with iron deposition to cancer. Studies on malignant diseases of the breast reported irregular expression in genes associated with iron metabolism. The variations are related to findings that have prognostic significance. This study evaluated the relationship of the expression levels of transferrin receptor 1 (TFRC), iron regulatory protein 1 (IRP1), hepcidin (HAMP), ferroportin 1 (FPN1), hemojuvelin (HFE2), matriptase 2 (TMPRSS6), and miR-122 genes in the normal and malignant tissues of breast cancer patients.

Methods & Results

The normal and malignant tissues from 75 women with breast malignancies were used in this study. The patients did not receive any treatment previously. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used in figuring the levels of gene expression associated with iron metabolism. When the malignant and normal tissues gene expression levels were analyzed, expression of TFRC increased (1.586-fold); IRP1 (0.594 fold) and miR-122 (0.320 fold) expression decreased; HAMP, FPN1, HFE2, and TMPRSS6 expressions did not change. FPN1 and IRP1 had a positive association, and this association was statistically significant (r = 0.266; p = 0.022). IRP1 and miR-122 had a positive association, and this association had statistical significance (r = 0.231; p = 0.048).

Conclusions

Our study portrayed the important association between genes involved in iron hemostasis and breast malignancy. The results could be used to establish new diagnostic techniques in the management of breast malignancies. The alterations in the metabolism of malignant breast cells with normal breast cells could be utilized to achieve advantages in treatment.

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Data Availability

The data of the study are available upon request from the corresponding author.

References

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

    Article  Google Scholar 

  2. Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A (2021) Breast Cancer—epidemiology, risk factors, classification, prognostic markers, and current treatment Strategies—An updated review. Cancers (Basel) 13:4287. https://doi.org/10.3390/cancers13174287

    Article  CAS  PubMed  Google Scholar 

  3. Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y (2016) Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends Biochem Sci 41:274–286. https://doi.org/10.1016/j.tibs.2015.11.012

    Article  CAS  PubMed  Google Scholar 

  4. Silva B, Faustino P (2015) An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 1852:1347–1359. https://doi.org/10.1016/j.bbadis.2015.03.011

    Article  CAS  PubMed  Google Scholar 

  5. Huang N, Zhan LL, Cheng Y, Wang XL, Wei YX, Wang Q, Li WJ (2020) TfR1 extensively regulates the expression of genes Associated with Ion Transport and Immunity. Curr Med Sci 40:493–501. https://doi.org/10.1007/s11596-020-2208-y

    Article  CAS  PubMed  Google Scholar 

  6. Sanchez M, Galy B, Schwanhaeusser B, Blake J, Bähr-Ivacevic T, Benes V, Selbach M, Muckenthaler MU, Hentze MW (2011) Iron regulatory protein-1 and – 2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins blood. 118:e168–e179. https://doi.org/10.1182/blood-2011-04-343541

  7. Liang L, Liu H, Yue J, Liu LR, Han M, Luo LL, Zhao YL, Xiao H (2017) Association of single-nucleotide polymorphism in the Hepcidin promoter gene with susceptibility to Extrapulmonary Tuberculosis. Genet Test Mol Biomarkers 21:351–356. https://doi.org/10.1089/gtmb.2016.0300

    Article  CAS  PubMed  Google Scholar 

  8. Nemeth E, Ganz T (2021) Hepcidin-Ferroportin Interaction controls systemic Iron homeostasis. Int J Mol Sci 22:6493. https://doi.org/10.3390/ijms22126493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiao X, Alfaro-Magallanes VM, Babitt JL (2020) Bone morphogenic proteins in iron homeostasis. Bone 138:115495. https://doi.org/10.1016/j.bone.2020.115495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Castoldi M, Vujic Spasic M, Altamura S, Elmén J, Lindow M, Kiss J, Stolte J, Sparla R, D’Alessandro LA, Klingmüller U, Fleming RE, Longerich T, Gröne HJ, Benes V, Kauppinen S, Hentze MW, Muckenthaler MU (2011) The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J Clin Invest 121:1386–1396. https://doi.org/10.1172/JCI44883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(– Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  12. Miller LD, Coffman LG, Chou JW, Black MA, Bergh J, D’Agostino R Jr, Torti SV, Torti FM (2011) An Iron Regulatory Gene signature predicts outcome in breast Cancer. Cancer Res 71:6728–6737. https://doi.org/10.1158/0008-5472.CAN-11-1870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Habashy HO, Powe DG, Staka CM, Rakha EA, Ball G, Green AR, Aleskandarany M, Paish EC, Douglas Macmillan R, Nicholson RI, Ellis IO, Gee JM (2010) Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer Res Treat 119:283–293. https://doi.org/10.1007/s10549-009-0345-x

    Article  CAS  PubMed  Google Scholar 

  14. Jiang XP, Elliott RL, Head JF (2010) Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res 30:759–765 PMID:20392994

    CAS  PubMed  Google Scholar 

  15. Chen F, Yumei F, Jiajie H, Liu B, Zhang B, Shang Y, Chang Y, Cao P, Ke Tan (2021) Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer. Aging 13:21671–21699. https://doi.org/10.18632/aging.203512

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wang J, Pantopoulos K (2002) Conditional derepression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Mol Cell Biol 22:4638–4651. https://doi.org/10.1128/MCB.22.13.4638-4651.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deng Z, Manz DH, Torti SV, Torti FM Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth. Oncotarget 8:82231–82243.

  18. Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie L, Attili D, Pant A, Gyor_yB, Zhan M, Carter-Su C (2017) (2016) Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis. Cell Metab 24:447–446. https://doi:10.1016/j.cmet.2016.07.015

  19. Luo QQ, Wang D, Yu MY, Zhu L (2011) Effect of hypoxia on the expression of iron regulatory proteins 1 and the mechanisms involved. IUBMB Life 63:120–128. https://doi.org/10.1002/iub.419

    Article  CAS  PubMed  Google Scholar 

  20. Aschemeyer S, Qiao B, Stefanova D, Valore EV, Sek AC, Ruwe TA, Vieth KR, Jung G, Casu C, Rivella S (2017) Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 131:899–910. https://doi.org/10.1182/blood-2017-05-786590

    Article  PubMed  Google Scholar 

  21. Vela D, Vela-Gaxha Z (2018) Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp Mol Med 50:e436. https://doi.org/10.1038/emm.2017.273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shen Y, Li X, Su Y, Badshah SA, Zhang B, Xue Y, Shang P (2019) HAMP downregulation contributes to aggressive hepatocellular carcinoma via mechanism mediated by Cyclin4-Dependent Kinase-1/STAT3 pathway. Diagnostics (Basel) 9:48. https://doi.org/10.3390/diagnostics9020048

    Article  CAS  PubMed  Google Scholar 

  23. Zhang S, Chen Y, Guo W, Yuan L, Zhang D, Xu Y, Nemeth E, Ganz T, Liu S (2014) Disordered hepcidin–ferroportin signaling promotes breast cancer growth. Cell Signal 26:2539–2550. https://doi.org/10.1016/j.cellsig.2014.07.029

    Article  CAS  PubMed  Google Scholar 

  24. Pinnix ZK, Miller LD, Wang W, D’Agostino R Jr, Kute T, Willingham MC, Hatcher H, Tesfay L, Sui G, Di X, Torti SV, Torti FM (2010) Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2:43ra56. https://doi.org/10.1126/scitranslmed.3001127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen S, Zhu B, Yu L (2006) In silico comparison of gene expression levels in ten human tumor types reveals candidate genes associated with carcinogenesis. Cytogenet Genome Res 112:53–59. https://doi.org/10.1159/000087513

    Article  CAS  PubMed  Google Scholar 

  26. Maxson JE, Chen J, Enns CA, Zhang AS (2010) Matriptase-2-and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down regulation of hepcidin expression. J Biol Chem 285:39021–39028. https://doi.org/10.1074/jbc.M110.183160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mete M, Trabulus DC, Talu CK, Ozoran E, Mutlu T, Tekin B, Guven M (2020) An investigation of the relationship between TMPRSS6 gene expression, genetic variants and clinical findings in breast cancer. Mol Biol Rep 47:4225–4231. https://doi.org/10.1007/s11033-020-05498-0

    Article  CAS  PubMed  Google Scholar 

  28. Parr C, Sanders AJ, Davies G, Martin T, Lane J, Mason MD, Mansel RE, Jiang WG (2007) Matriptase-2 inhibits breast tumor growth and invasion and correlates with favorable prognosis for breast cancer patients. Clin Cancer Res 13:3568–5576. https://doi.org/10.1158/1078-0432.CCR-06-2357

    Article  CAS  PubMed  Google Scholar 

  29. Overall CM, Tam EM, Kappelhoff R, Connor A, Ewart T, Morrison CJ (2004) Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors. Biol Chem 385:493–504. https://doi.org/10.1515/BC.2004.058

    Article  CAS  PubMed  Google Scholar 

  30. Gitlin-Domagalska A, Mangold M, Dębowski D, Ptaszyńska N, Łęgowska A, Gütschow M, Rolka K (2018) Matriptase-2: monitoring and inhibiting its proteolytic activity. Future Med Chem 10:1–8. https://doi.org/10.4155/fmc-2018-0346

    Article  CAS  Google Scholar 

  31. Clement JH, Sänger J, Höffken K (1999) Expression of bone morphogenetic protein 6 in normal mammary tissue and breast cancer cell lines and its regulation by epidermal growth factor. Int J Cancer 80:250–256. https://doi.org/10.1002/(sici)1097-0215(19990118)80:2<250::aid-ijc14>3.0.co;2-d

    Article  CAS  PubMed  Google Scholar 

  32. Feinberg MW, Moore KJ (2016) MicroRNA regulation of atherosclerosis. Circ Res 118:703–720. https://doi.org/10.1161/CIRCRESAHA.115.306300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yan Y, Zhang F, Fan Q, Li X, Zhou K (2014) Breast cancer-specific TRAIL expression mediated by miRNA response elements of let-7 and miR-122. Neoplasma 61:672–679. https://doi.org/10.4149/neo_2014_082

    Article  CAS  PubMed  Google Scholar 

  34. -Wang B, Wang H, Yang Z (2012) MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS ONE 7:e47053. https://doi.org/10.1371/journal.pone.0047053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ergün S, Ulasli M, Igci YZ, Igci M, Kırkbes S, Borazan E, Balik A, Yumrutaş Ö, Camci C, Cakmak EA, Arslan A, Oztuzcu S (2015) The association of the expression of mir-122-5p and its target ADAM10 with human breast cancer. Mol Biol Rep 42:497–505. https://doi.org/10.1007/s11033-014-3793-2

    Article  CAS  PubMed  Google Scholar 

  36. Saleh AA, Soliman SE, Habib MSE, Gohar SF, Abo-Zeid GS (2019) Potential value of circulatory microRNA122 gene expression as a prognostic and metastatic prediction marker for breast cancer. Mol Biol Rep 46:2809–2818. https://doi.org/10.1007/s11033-019-04727-5

    Article  CAS  PubMed  Google Scholar 

  37. Shao X, Cao F, Tao M (2017) The clinical value of hepcidin in breast cancer and its bone metastasis. Ann Clin Lab Sci 47:120–128

    CAS  PubMed  Google Scholar 

  38. Shen Y, Li X, Dong D, Zhang B, Xue Y, Shang P (2018) Transferrin receptor 1 in cancer: a new sight for cancer therapy. Am J Cancer Res 8:916–931

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Scientific Research Project Coordination Unit of Istanbul University-Cerrahpasa funded the research, Project No. 22092.

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Authors and Affiliations

  1. Medical Biology and Genetics, Faculty of Medicine, Istanbul Arel University, Istanbul, 34010, Turkey

    Tuba Mutlu

  2. Department of General Surgery, Koc University Hospital, 34365, Istanbul, Turkey

    Emre Ozoran

  3. Department of General Surgery, Istanbul Education Research Hospital, 34098, Istanbul, Turkey

    Didem Can Trabulus

  4. Department of Pathology, Istanbul Education Research Hospital, 34098, Istanbul, Turkey

    Canan Kelten Talu

  5. Department of Medical Biology, Cerrahpasa Medicine Faculty, Istanbul University-Cerrahpasa, 34098, Istanbul, Turkey

    Duygu Erhan, Meltem Mete & Mehmet Guven

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  1. Tuba Mutlu
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Correspondence to Mehmet Guven.

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Compliance with ethical standards

The authors declare no conflict of interest.

The ethical approval was obtained from Istanbul University-Cerrahpasa Cerrahpasa Medical School Institutional Review Board on June 6th, 2016 with the serial code 214246. All of the procedures on human participants were in accordance with the declaration of Helsinki in 1964, its amendments, and parallel ethical standards.

All the patients in this study provided informed consent before inclusion.

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Mutlu, T., Ozoran, E., Trabulus, D.C. et al. Expression of genes related to iron homeostasis in breast cancer. Mol Biol Rep 50, 5157–5163 (2023). https://doi.org/10.1007/s11033-023-08433-1

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