Skip to main content

Advertisement

SpringerLink
Log in

Peroxisome proliferator-activated receptor ɑ (PPARɑ)–cytochrome P450 epoxygenases-soluble epoxide hydrolase axis in ER + PR + HER2− breast cancer

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Fibrates belong to a group of ligands of peroxisome proliferator-activated receptor alpha (PPARα), which play a role in the regulation of CYP epoxygenases and soluble epoxide hydrolase (sEH), key enzymes in the metabolism of biologically highly active epoxyeicosatrienoic acids (EETs). We demonstrated that low doses of fibrates stimulate proliferation of the MCF7 cell line, while high doses suppress it. The increase in cell proliferation was accompanied by an increase in CYP epoxygenases and decrease in sEH levels. The overall level of PPARα remained same after low-dose fibrate stimulation; however, there was a significant shift of the receptor to the cell nucleus. PPARα expression was further demonstrated by immunohistochemistry in both carcinoma and healthy breast tissue samples both in the cytoplasm and in the nuclei. We have also observed higher nuclear PPARα positivity in tumor tissues. Although our results obtained for MCF7 cells suggest the potential role of PPARα in cell proliferation, we did not find an association between nuclear localization of PPARα and the expression of proliferation marker Ki-67 in tumor tissues. The exact role of PPARα in carcinogenesis still remains unclear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade (in eng). Cell 83:835–839

    Article  CAS  Google Scholar 

  2. Hsu MH, Palmer CN, Song W, Griffin KJ, Johnson EF (1998) A carboxyl-terminal extension of the zinc finger domain contributes to the specificity and polarity of peroxisome proliferator-activated receptor DNA binding (in eng). J Biol Chem 273:27988–27997. https://doi.org/10.1074/jbc.273.43.27988

    Article  CAS  PubMed  Google Scholar 

  3. Gervois P, Chopin-Delannoy S, Fadel A, Dubois G, Kosykh V, Fruchart JC, Najib J, Laudet V, Staels B (1999) Fibrates increase human REV-ERBalpha expression in liver via a novel peroxisome proliferator-activated receptor response element (in eng). Mol Endocrinol (Baltimore, Md) 13:400–409. https://doi.org/10.1210/mend.13.3.0248

    Article  CAS  Google Scholar 

  4. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors (in eng). Nature 358:771–774. https://doi.org/10.1038/358771a0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Peters JM, Shah YM, Gonzalez FJ (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention (in eng). Nat Rev Cancer 12:181–195. https://doi.org/10.1038/nrc3214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schoonjans K, Staels B, Auwerx J (1996) Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression (in eng). J Lipid Res 37:907–925

    CAS  PubMed  Google Scholar 

  7. Shipman KE, Strange RC, Ramachandran S (2016) Use of fibrates in the metabolic syndrome: a review (in eng). World J Diabetes 7:74–88. https://doi.org/10.4239/wjd.v7.i5.74

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zambon A, Cusi K (2007) The role of fenofibrate in clinical practice (in eng). Diabetes Vasc Dis Res 4(Suppl 3):S15–S20. https://doi.org/10.3132/dvdr.2007.053

    Article  Google Scholar 

  9. Milionis H (2014) Combining a statin with a fibrate versus fibrate monotherapy: efficacious but safe? (in eng). Exp Opin Drug Safety 13:267–269. https://doi.org/10.1517/14740338.2014.887679

    Article  CAS  Google Scholar 

  10. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism (in eng). Circulation 98:2088–2093

    Article  CAS  Google Scholar 

  11. Goya K, Sumitani S, Xu X, Kitamura T, Yamamoto H, Kurebayashi S, Saito H, Kouhara H, Kasayama S, Kawase I (2004) Peroxisome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells (in eng). Arterioscler Thromb Vasc Biol 24:658–663. https://doi.org/10.1161/01.atv.0000118682.58708.78

    Article  CAS  PubMed  Google Scholar 

  12. Yoon M (2009) The role of PPARalpha in lipid metabolism and obesity: focusing on the effects of estrogen on PPARalpha actions (in eng). Pharmacol Res 60:151–159. https://doi.org/10.1016/j.phrs.2009.02.004

    Article  CAS  PubMed  Google Scholar 

  13. Contreras AV, Torres N, Tovar AR (2013) PPAR-α as a key nutritional and environmental sensor for metabolic adaptation (in eng). Adv Nutr 4:439–452. https://doi.org/10.3945/an.113.003798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koh EH, Kim MS, Park JY, Kim HS, Youn JY, Park HS, Youn JH, Lee KU (2003) Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation (in eng). Diabetes 52:2331–2337. https://doi.org/10.2337/diabetes.52.9.2331

    Article  CAS  PubMed  Google Scholar 

  15. Aasum E, Belke DD, Severson DL, Riemersma RA, Cooper M, Andreassen M, Larsen TS (2002) Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator (in eng). Am J Physiol Heart Circ Physiol 283:H949–H957. https://doi.org/10.1152/ajpheart.00226.2001

    Article  CAS  PubMed  Google Scholar 

  16. Park CW, Zhang Y, Zhang X, Wu J, Chen L, Cha DR, Su D, Hwang MT, Fan X, Davis L, Striker G, Zheng F, Breyer M, Guan Y (2006) PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice (in eng). Kidney Int 69:1511–1517. https://doi.org/10.1038/sj.ki.5000209

    Article  CAS  PubMed  Google Scholar 

  17. Urbanska K, Pannizzo P, Grabacka M, Croul S, Del Valle L, Khalili K, Reiss K (2008) Activation of PPARalpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines (in eng). Int J Cancer 123:1015–1024. https://doi.org/10.1002/ijc.23588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnes CM, Fannon M, Laforme AM, Chaponis DM, Folkman J, Kieran MW (2008) PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition (in eng). Proc Natl Acad Sci USA 105:985–990. https://doi.org/10.1073/pnas.0711281105

    Article  PubMed  Google Scholar 

  19. Liang H, Kowalczyk P, Junco JJ, Klug-De Santiago HL, Malik G, Wei SJ, Slaga TJ (2014) Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARalpha receptors (in eng). Mol Carcinog 53:753–763. https://doi.org/10.1002/mc.22029

    Article  CAS  PubMed  Google Scholar 

  20. Grabacka M, Plonka PM, Urbanska K, Reiss K (2006) Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt (in eng). Clin Cancer Res 12:3028–3036. https://doi.org/10.1158/1078-0432.ccr-05-2556

    Article  CAS  PubMed  Google Scholar 

  21. Cizkova K, Steigerova J, Gursky J, Ehrmann J (2016) Stimulating effect of normal-dosing of fibrates on cell proliferation: word of warning (in eng). Lipids Health Dis 15:164. https://doi.org/10.1186/s12944-016-0335-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Suchanek KM, May FJ, Robinson JA, Lee WJ, Holman NA, Monteith GR, Roberts-Thomson SJ (2002) Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231 (in eng). Mol Carcinog 34:165–171. https://doi.org/10.1002/mc.10061

    Article  CAS  PubMed  Google Scholar 

  23. Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors (in eng). Cancer Res 65:4707–4715. https://doi.org/10.1158/0008-5472.can-04-4173

    Article  CAS  PubMed  Google Scholar 

  24. Shen GF, Jiang JG, Fu XN, Wang DW (2008) Promotive effects of epoxyeicosatrienoic acids (EETs) on proliferation of tumor cells (in chi). Ai zheng = Aizheng = Chinese J Cancer 27:1130–1136

    CAS  Google Scholar 

  25. Cizkova K (2018) Expression of cytochrome P450 epoxygenases and soluble epoxide hydrolase is regulated by hypolipidemic drugs in dose-dependent manner (in eng). Toxicol Appl Pharmacol 355:156–163. https://doi.org/10.1016/j.taap.2018.06.025

    Article  CAS  PubMed  Google Scholar 

  26. Wei X, Zhang D, Dou X, Niu N, Huang W, Bai J, Zhang G (2014) Elevated 14,15- epoxyeicosatrienoic acid by increasing of cytochrome P450 2C8, 2C9 and 2J2 and decreasing of soluble epoxide hydrolase associated with aggressiveness of human breast cancer (in eng). BMC Cancer 14:841. https://doi.org/10.1186/1471-2407-14-841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Holliday DL, Speirs V (2011) Choosing the right cell line for breast cancer research (in eng). Breast Cancer Res BCR 13:215. https://doi.org/10.1186/bcr2889

    Article  PubMed  Google Scholar 

  28. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AFH (2012) Evaluation and treatment of hypertriglyceridemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 97:2969–2989. https://doi.org/10.1210/jc.2011-3213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Umemoto T, Fujiki Y (2012) Ligand-dependent nucleo-cytoplasmic shuttling of peroxisome proliferator-activated receptors, PPARalpha and PPARgamma (in eng). Genes Cells 17:576–596. https://doi.org/10.1111/j.1365-2443.2012.01607.x

    Article  CAS  PubMed  Google Scholar 

  30. Hong F, Pan S, Guo Y, Xu P, Zhai Y (2019) PPARs as nuclear receptors for nutrient and energy metabolism (in eng). Molecules 24:2545. https://doi.org/10.3390/molecules24142545

    Article  CAS  PubMed Central  Google Scholar 

  31. Pyper SR, Viswakarma N, Yu S, Reddy JK (2010) PPARalpha: energy combustion, hypolipidemia, inflammation and cancer (in eng). Nucl Recep Signal 8:e002. https://doi.org/10.1621/nrs.08002

    Article  CAS  Google Scholar 

  32. Rakhshandehroo M, Knoch B, Muller M, Kersten S (2010) Peroxisome proliferator-activated receptor alpha target genes (in eng). PPAR Res. https://doi.org/10.1155/2010/612089

    Article  PubMed  PubMed Central  Google Scholar 

  33. Baker BG, Ball GR, Rakha EA, Nolan CC, Caldas C, Ellis IO, Green AR (2013) Lack of expression of the proteins GMPR2 and PPARalpha are associated with the basal phenotype and patient outcome in breast cancer (in eng). Breast Cancer Res Treat 137:127–137. https://doi.org/10.1007/s10549-012-2302-3

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank to Lucie Voznakova for excellent technical support.

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 3, 779 00, Olomouc, Czech Republic

    Zdenek Tauber & Katerina Cizkova

  2. Laboratory of Molecular Pathology, Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 3, 779 00, Olomouc, Czech Republic

    Marketa Koleckova

Authors
  1. Zdenek Tauber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marketa Koleckova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katerina Cizkova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katerina Cizkova.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table S1: Patient characteristics (XLSX 9 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tauber, Z., Koleckova, M. & Cizkova, K. Peroxisome proliferator-activated receptor ɑ (PPARɑ)–cytochrome P450 epoxygenases-soluble epoxide hydrolase axis in ER + PR + HER2− breast cancer. Med Mol Morphol 53, 141–148 (2020). https://doi.org/10.1007/s00795-019-00240-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-019-00240-7

Keywords

Search

Navigation