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Body mass index and γ-glutamyl transferase expression in normal and cancerous breast tissue

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Abstract

Background

Localized to cell membrane, γ-glutamyl transferase (GGT) is a reliable marker for the evaluation of cell distress occurring in several pathological conditions including obesity, metabolic syndrome, and cancer. In particular, high GGT serum levels are associated with breast cancer incidence and progression.

Methods

The tissue expression of GGT1, the gene coding for GGT, was investigated in silico in a large case series of paired samples of breast cancer and adjacent histologically normal (HN) tissue, and in a collection of healthy breast tissues from reduction mammoplasty. The association of GGT1 with patient’s body mass index (BMI), and the relationship between GGT1 and a panel of genes involved in apoptosis, IGF-1 signaling, or coding for adipokines and adipokine receptors were also investigated.

Results

GGT1 expression was significantly higher in tumor than in the adjacent HN tissue (P = 0.0002). Unexpectedly, the expression of GGT1 was inversely associated with BMI in normal and HN tissue, whereas no correlation was found in cancerous tissue. In all tissues, GGT1 correlated positively with TP53 and negatively with BCL2 and LEPR, whereas only in normal and HN tissue GGT1 correlated positively with IGF1R. The linear regression model, adjusted for BMI, showed no confounding effect on any correlation, except for the correlation of GGT1 with LEPR in normal tissue from healthy women.

Conclusions

Even if present results provide interesting insights on the still elusive mechanism(s) underlying the association between obesity and epithelial cell proliferation, possibly promoting neoplastic transformation, such relationship deserves further investigation in other independent datasets.

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Data availability

Original data are available through the NCBI Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nhi.gov/geo/).

Abbreviations

ADIPOQ:

Adiponectin

ADIPOR1:

Adiponectin receptor 1

ADIPOR2:

Adiponectin receptor 2

APLN:

Apelin

APLNR:

Apelin receptor

BCL2:

Bcl2, apoptosis regulator

BMI:

Body mass index

CCRL2:

Chemokine (C–C Motif) receptor-like 2

CDH13:

Cadherin 13

GEO:

Gene expression omnibus

FAS:

Fas (TNF receptor superfamily, member 6)

FASLG:

Fas ligand

GGT:

γ-Glutamyl transferase

GGT1:

γ-Glutamyl transferase 1

GPER1:

G protein-coupled estrogen receptor 1

HN:

Histologically normal

IGF-1:

Insulin-like growth factor-1

IGF1R:

Insulin-like growth factor-1 receptor

IGFBP:

Insulin-like growth factor binding protein

LEP:

Leptin

LEPR:

Leptin receptor

RARRES2:

Retinoic acid receptor responder 2

TNF:

Tumor necrosis factor

TP53:

Tumor protein p53

TU:

Tumor

References

  1. Withfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci. 2001;38:263–355.

    Article  Google Scholar 

  2. Hall AG. The role of glutathione in the regulation of apoptosis. Eur J Clin Invest. 1999;29:238–45.

    Article  CAS  Google Scholar 

  3. Jousilahti P, Rastenyte D, Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke. 2000;31:1851–5.

    Article  CAS  Google Scholar 

  4. Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2007;27:127–33.

    Article  CAS  Google Scholar 

  5. Nilssen O, Forde OH, Brenn T. The tromso study. Distribution and population determinants of γ-glutamyltransferase. Am J Epidemiol. 1990;132:318–26.

    Article  CAS  Google Scholar 

  6. Iwasaki T, Yoneda M, Kawasaki S, et al. Hepatic fat content-independent association of the serum level of γ-glutamyltransferase with visceral adiposity, but not subcutaneous adiposity. Diabetes Res Clin Pract. 2008;79:e13–e1414.

    Article  CAS  Google Scholar 

  7. Lim JS, Lee DH, Park JY, ** SH, Jacobs DR. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem. 2007;53:1092–8.

    Article  CAS  Google Scholar 

  8. Fentiman IS, Allen DS. γ-glutamyl transferase and breast cancer risk. Br J Cancer. 2010;103:90–3.

    Article  CAS  Google Scholar 

  9. Staudigl C, Concin N, Grimm C, et al. Prognostic relevance of pretherapeutic gamma-glutamyltransferase in patients with primary metastatic breast cancer. PLoS ONE. 2015;10:e0125317.

    Article  Google Scholar 

  10. Balendiran GK, Dabur R, Fraser D. The role of glutathione in cancer. Cell Biochem Function. 2004;22:343–52.

    Article  CAS  Google Scholar 

  11. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30:445–600.

    Article  CAS  Google Scholar 

  12. Quigley DA, Tahiri A, Lüders T, et al. Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue. OncoImmunology. 2017;6:e1356142.

    Article  Google Scholar 

  13. Sun X, Casbas-Hernandez P, Bigelow C, et al. Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat. 2012;131:1003–122.

    Article  CAS  Google Scholar 

  14. Friesen C, Kiess Y, Debatin K-M. A critical role of glutathione in determining apoptosis sensitivity and resistance in leukaemia cells. Cell Death Differ. 2004;11:S73–S85.

    Article  CAS  Google Scholar 

  15. Rosato V, Borsetti C, Salamini R, et al. Metabolic syndrome and the risk of breast cancer in postmenopausal women. Ann Oncol. 2011;22:2687–92.

    Article  CAS  Google Scholar 

  16. Pierobon M, Frankenfeld CL. Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;137:307–14.

    Article  Google Scholar 

  17. Bender R, Lange S. Adjusting for multiple testing—when and how? J Clin Epidemiol. 2001;54:343–9.

    Article  CAS  Google Scholar 

  18. Dawson J, Smith GD, Boak J, Peters TJ. Gamma-glutamyltransferase in human and mouse breast tumors. Clin Chim Acta. 1979;96:37–42.

    Article  CAS  Google Scholar 

  19. Durham JR, Frierson HF Jr, Hanigan MH. Gamma-glutamyl transpeptidase immunoreactivity in benign and malignant breast tissue. Breast Cancer Res Treat. 1997;45:55–62.

    Article  CAS  Google Scholar 

  20. Fiala S, Trout EC Jr, Teague CA, Fiala ES. gamma-Glutamyltransferase, a common marker of human epithelial tumors? Cancer Detect Prev. 1980;3:471–85.

    CAS  PubMed  Google Scholar 

  21. Levine SE, Budwit DA, Michalopoulos GK, Georgiade GS, McCarty KS Jr. Normal breast epithelium and nondysplastic gamma-Glutamyl transpeptidase activity in benign and malignant human mammary epithelial lesions. Histochemical evaluation. Arch Pathol Lab Med. 1983;107:423–7.

    CAS  PubMed  Google Scholar 

  22. Lelievre SA. Tissue polarity-dependent control of mammary epithelial homeostasis and cancer development: an epigenetic perspective. J Mammary Gland Biol Neoplasia. 2010;15:49–63.

    Article  Google Scholar 

  23. Feigin ME, Akshinthala SD, Araki K, et al. Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Res. 2014;74:3180–94.

    Article  CAS  Google Scholar 

  24. Coradini D, Oriana S. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation. Chin J Cancer. 2014;33:51–67.

    Article  CAS  Google Scholar 

  25. Halaoui R, McCaffrey L. Rewiring cell polarity signaling in cancer. Oncogene. 2015;34:939–50.

    Article  CAS  Google Scholar 

  26. Chandramouly G, Abad PC, Knowles DW, Lelievre SA. The control of tissue architecture over nuclear organization is crucial for epithelial cell fate. J Cell Sci. 2007;120:1596–606.

    Article  CAS  Google Scholar 

  27. Vidi PA, Chandramouly G, Gray M, et al. Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response. J Cell Sci. 2012;125:350–61.

    Article  CAS  Google Scholar 

  28. Ray A. Adipokine leptin in obesity-related pathology of breast cancer. J Biosci. 2012;37:289–94.

    Article  Google Scholar 

  29. Hu X, Juneja SC, Maihle NJ, et al. Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst. 2002;94:1704–11.

    Article  CAS  Google Scholar 

  30. Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N. Leptin signaling in breast cancer: an overview. J Cell Biochem. 2008;105:956–64.

    Article  CAS  Google Scholar 

  31. Tenvooren I, Jenks MZ, Rashid H, et al. Elevated leptin disrupts epithelial polarity and promotes premalignant alterations in the mammary gland. Oncogene. 2019;38:3855–70.

    Article  CAS  Google Scholar 

  32. Saxena NK, Sharma D. Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia. 2013;18:309–20.

    Article  Google Scholar 

  33. Wang Z, Greeley GH Jr, Qiu S. Immunohistochemical localization of apelin in human normal breast and breast carcinoma. J Mol Histol. 2008;39:121–4.

    Article  CAS  Google Scholar 

  34. Deeks S, Richards J, Nandi S. Maintenance of normal rat mammary epithelial cells by insulin and insulin-like growth factor 1. Exp Cell Res. 1988;174:448–60.

    Article  CAS  Google Scholar 

  35. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89.

    Article  CAS  Google Scholar 

  36. Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006;17:328–36.

    Article  CAS  Google Scholar 

  37. Lautenbach A, Budde A, Wrann CD, et al. Obesity and the associated mediators leptin, estrogen and IGF-I enhance the cell proliferation and early tumorigenesis of breast cancer cells. Nutr Cancer. 2009;61:484–91.

    Article  CAS  Google Scholar 

  38. Saxena NK, Taliaferro-Smith L, Knight BB, et al. Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res. 2008;68:9712–22.

    Article  CAS  Google Scholar 

  39. Bhargava R, Beriwal S, McManus K, Dabbs DJ. Insulin-like growth factor receptor-1 (IGF-1R) expression in normal breast, proliferative breast lesions, and breast carcinoma. Appl Immunohistochem Mol Morphol. 2011;19:218–25.

    Article  CAS  Google Scholar 

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Funding

The authors received no specific founding for this study.

Author information

Authors and Affiliations

  1. Laboratory of Medical Statistics and Biometry, ‘Giulio A. Maccacaro’, Department of Clinical Sciences and Community Health, University of Milan, Campus Cascina Rosa, Milan, Italy

    Danila Coradini, Simone Gambazza & Federico Ambrogi

  2. Senology Center, Istituto Sacra Famiglia, Cesano Boscone, Milan, Italy

    Saro Oriana

Authors
  1. Danila Coradini
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  2. Simone Gambazza
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  3. Saro Oriana
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  4. Federico Ambrogi
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Contributions

DC conceived the study, wrote the paper and prepared the figures. SO assisted in data interpretation and manuscript preparation. FA and SG analyzed the data, and assisted in data interpretation and manuscript preparation.

Corresponding author

Correspondence to Danila Coradini.

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Conflict of interest

The authors declare that they have no conflict of interest.

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All authors listed above have reviewed and verified the manuscript for accuracy. All authors have consented to be an author and publish the manuscript.

Ethical approval and consent to participate

Present study was performed using publicly-available datasets retrieved from GEO database. As regards GSE70947, the original study was approved by REC SouthEast (Regional Ethical Committee for Medical and Health Research Ethics) and by the Ethical Committee for Aarhus county and by “Datatilsynet” (The Data Inspectorate, an independent administrative body under the Ministry of Government Administration and Reform), whereas as regards GSE33526, the original study was approved by the Institutional Review Boards at Baystate Medical Center and University of Massachusetts Amherst. In both cases, all patients consented to provide excess tissues not needed for research purposes.

Human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Coradini, D., Gambazza, S., Oriana, S. et al. Body mass index and γ-glutamyl transferase expression in normal and cancerous breast tissue. Breast Cancer 27, 850–860 (2020). https://doi.org/10.1007/s12282-020-01080-5

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  • DOI: https://doi.org/10.1007/s12282-020-01080-5

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