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An investigation of the relationship between TMPRSS6 gene expression, genetic variants and clinical findings in breast cancer

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Abstract

Breast cancer is one of the most common types of cancer among women worldwide. The TMPRSS6 (Transmembrane Serine Protease 6) gene encodes matriptase-2, which plays an important role in iron hemostasis as the hepcidin regulator and may play a role in breast cancer susceptibility. In this study, we examined the expression levels of the TMPRSS6 gene in healthy tissues and tumor tissues of breast cancer patients; and the relationship between these levels and pathological findings. The relationship between TMPRSS6 polymorphisms (rs733655, rs5756506, rs2413450, rs855791, rs2235324, rs4820268) and patients’ hematological parameters. The gene expression study encompassed 47 breast cancer patients and the gene polymorphism study consisted of 181 breast cancer patients and 100 healthy controls. Gene expression analysis was performed by qRT-PCR. The genotyping of TMPRSS6 polymorphisms was performed by RT-PCR. TMPRSS6 gene expression levels in tumor tissues were found to be 1.88 times higher than the expression levels in the control tissues. We examined the relationship between TMPRSS6 gene expression levels and pathological data, statistically significant relationship was found between patient's estrogen receptor (ER) and HER2 findings and TMPRSS6 gene expression (respectively p = 0.02, p = 0.002). When the relationship between TMPRSS6 gene polymorphisms related genotypes distributions and hematological findings was investigated, a significant relationship was identified between mean corpuscular hemoglobin concentration (MCHC) parameter and the polymorphism of only the rs733655. According to our findings, the increase in TMPRSS6 gene expression in cancerous tissues shows that matriptase-2 may be effective in the cancer process. Thus TMPRSS6 gene polymorphisms may affect the disease process by affecting the blood parameters of patients.

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References

  1. Silvenberg E, Lubera J (1987) Cancer statistics. Cancer J Clin 37:2–19. https://doi.org/10.3322/canjclin.37.1.2

    Article  Google Scholar 

  2. Hartikainen JM, Tuhkanen H, Kataja V, Eskelinen M, Uusitupa M, Kosma VM, Mannermaa A et al (2006) Refinement of the 22q12-q13 breast cancer-associated region: evidence of TMPRSS6 as a candidate gene in an Eastern Finnish population. Clin Cancer Res 12:1454–1462. https://doi.org/10.1158/1078-0432.CCR-05-1417

    Article  CAS  PubMed  Google Scholar 

  3. Lang JC, Schuller DE (2001) Differential expression of a novel serine protease homologue in squamous cell carcinoma of the head and neck. Br J Cancer 84:237–243. https://doi.org/10.1054/bjoc.2000.1586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bugge TH, Antalis TM, Qingyu Wu (2009) Type II transmembrane serine proteases. J Biol Chem 284:23177–23181. https://doi.org/10.1074/jbc.R109.021006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Antalis TM, Buzza MS, Hodge KM, Hooper JD, Netzel-Arnett S (2010) The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem J 428:325–346. https://doi.org/10.1042/BJ20100046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX et al (2006) Evidence for a matriptase prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 281:32941–32945. https://doi.org/10.1074/jbc.C600208200

    Article  CAS  PubMed  Google Scholar 

  7. Stirnberg M, Maurer E, Arenz K, Babler A, Jahnen-Dechent W, Gütschow M (2015) Cell surface serine protease matriptase-2 suppresses fetuin-A/AHSG-mediated induction of hepcidin. Biol Chem 396:81–93. https://doi.org/10.1515/hsz-2014-0120

    Article  CAS  PubMed  Google Scholar 

  8. Xin Du, She E, Gelbart T, Truksa J, Lee P, Xia Y et al (2008) The serine protease TMPRSS6 is required to sense iron deficiency. Science 320(5879):1088–1092. https://doi.org/10.1126/science.1157121

    Article  CAS  Google Scholar 

  9. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR et al (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40:569–571. https://doi.org/10.1038/ng.130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP (2009) Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41:1173–1175. https://doi.org/10.1038/ng.456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D et al (2009) Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 41:1170–1172. https://doi.org/10.1038/ng.462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tanaka T, Roy CN, Yao W, Matteini A, Semba RD, Arking D et al (2010) A genome-wide association analysis of serum iron concentrations. Blood 115:94–96. https://doi.org/10.1182/blood-2009-07-232496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  Google Scholar 

  14. Hooper JD, Clements JA, Quigley JP, Antalis TM (2001) Type II transmembrane serine proteases insights into an emerging class of cell surface proteolytic enzymes. J Biol Chem 276:857–860. https://doi.org/10.1074/jbc.R000020200

    Article  CAS  PubMed  Google Scholar 

  15. Netzel-Arnett S, Hooper JD, Szabo R, Madison EL, Quigley JP, Bugge TH et al (2003) Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev 22:237–258. https://doi.org/10.1023/a:1023003616848

    Article  CAS  PubMed  Google Scholar 

  16. Parr C, Sanders AJ, Davies G, Martin T, Lane J, Mason MD, Mansel RE, Jiang WG et al (2007) Matriptase-2 inhibits breast tumor growth and invasion and correlates with favorable prognosis for breast cancer patients. Clin Cancer Res 13:3568–35576. https://doi.org/10.1158/1078-0432.CCR-06-2357

    Article  CAS  PubMed  Google Scholar 

  17. Overall CM, Tam EM, Kappelhoff R, Connor A, Ewart T, Morrison CJ et al (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 

  18. 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 

  19. Miller LD, Coffman LG, Chou JW, Black MA, Bergh J, D'Agostino R Jr et al (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 

  20. Tuhkanen H, Hartikainen JM, Soini Y, Velasco G, Sironen R, Nykopp TK et al (2013) Matriptase-2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triplenegative breast cancer. Int J Cancer 133:2334–2340. https://doi.org/10.1002/ijc.28254

    Article  CAS  PubMed  Google Scholar 

  21. Clements JA (2019) Preface to “Proteases in Cancer Progression and Metastasis” special issue. Cancer Metastasis Rev 38:331–332. https://doi.org/10.1007/s10555-019-09817-1

    Article  PubMed  Google Scholar 

  22. Kauppinen JM, Kosma VM, Soini Y, Sironen R, Nissinen M, Nykopp TK et al (2010) ST14 gene variant and decreased matriptase protein expression predict poor breast cancer survival. Cancer Epidemiol Biomark Prev 19:2133–2142. https://doi.org/10.1158/1055-9965.EPI-10-0418

    Article  CAS  Google Scholar 

  23. Partanen JI, Tervonen TA, Myllynen M, Lind E, Imai M, Katajisto P et al (2012) Tumor suppressor function of liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Proc Natl Acad Sci USA 109:E388–397. https://doi.org/10.1073/pnas.1120421109

    Article  PubMed  Google Scholar 

  24. Alarmo EL, Kallioniemi A (2010) Bone morphogenetic proteins in breast cancer: dual role in tumourgenesis? Endocr Relat Cancer 17:R123–139. https://doi.org/10.1677/ERC-09-0273

    Article  CAS  PubMed  Google Scholar 

  25. Katsuta E, Maawy AA, Yan L, Takabe K (2019) High expression of bone morphogenetic protein (BMP) 6 and BMP7 are associated with higher immune cell infiltration and better survival in estrogen receptor-positive breast cancer. Oncol Rep 42:1413–1421. https://doi.org/10.3892/or.2019.7275

    Article  CAS  PubMed Central  Google Scholar 

  26. 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

    Article  CAS  Google Scholar 

  27. Schwaninger R, Rentsch CA, Wetterwald A, van der Horst G, van Bezooijen RL, van der Pluijm G et al (2007) Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am J Pathol 170:160–175. https://doi.org/10.2353/ajpath.2007.051276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang S, Du J, Wang Z, Yuan W, Qiao Y, Zhang M et al (2007) BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells. BMC Cancer 7:211. https://doi.org/10.1186/1471-2407-7-211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ganesh SK, Zakai NA, van Rooij FJA, Soranzo N, Smith AV, Nalls MA et al (2010) Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41:1191–1198. https://doi.org/10.1038/ng.466

    Article  CAS  Google Scholar 

  30. Kullo IJ, Ding K, Jouni H, Smith CY, Chute CG (2010) A genome-wide association study of red blood cell traits using the electronic medical record. PLoS ONE. https://doi.org/10.1371/journal.pone

    Article  PubMed  PubMed Central  Google Scholar 

  31. Soranzo N, Spector TD, Mangino M, Kühnel B, Rendon A et al (2009) A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41(11):1182–1190. https://doi.org/10.1038/ng.467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Research Fund of The University of Istanbul. Project Number: 49541.

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Authors and Affiliations

  1. Department of Medical Biology, Medical Faculty of Cerrahpasa, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Meltem Mete, Tuba Mutlu, Bulent Tekin & Mehmet Guven

  2. Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey

    Didem Can Trabulus

  3. Department of Pathology, Istanbul Training and Research Hospital, Istanbul, Turkey

    Canan Kelten Talu

  4. Department of General Surgery, Koc University Hospital, Istanbul, Turkey

    Emre Ozoran

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  1. Meltem Mete
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Correspondence to Mehmet Guven.

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Mete, M., Trabulus, D.C., Talu, C.K. et al. An investigation of the relationship between TMPRSS6 gene expression, genetic variants and clinical findings in breast cancer. Mol Biol Rep 47, 4225–4231 (2020). https://doi.org/10.1007/s11033-020-05498-0

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  • DOI: https://doi.org/10.1007/s11033-020-05498-0

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