Advertisement

Qualitative and quantitative differences in estrogen biotransformation in human breast glandular and adipose tissues: implications for studies using mammary biospecimens

  • Daniela Pemp
  • Carolin Kleider
  • Katja Schmalbach
  • René Hauptstein
  • Leo N. Geppert
  • Claudia Köllmann
  • Katja Ickstadt
  • Peter Eckert
  • Iva Neshkova
  • Rafael Jakubietz
  • Harald L. Esch
  • Leane LehmannEmail author
Toxicokinetics and Metabolism

Abstract

Because of its assumed role in breast cancer etiology, estrogen biotransformation (and interaction of compounds therewith) has been investigated in human biospecimens for decades. However, little attention has been paid to the well-known fact that large inter-individual variations exist in the proportion of breast glandular (GLT) and adipose (ADT) tissues and less to adequate tissue characterization. To assess the relevance of this, the present study compares estrogen biotransformation in GLT and ADT. GLT and ADT were isolated from 47 reduction mammoplasty specimens derived from women without breast cancer and were characterized histologically and by their percentages of oil. Levels of 12 unconjugated and five conjugated estrogens were analyzed by GC- and UHPLC–MS/MS, respectively, and levels of 27 transcripts encoding proteins involved in estrogen biotransformation by Taqman® probe-based PCR. Unexpectedly, one-third of specimens provided neat GLT only after cryosection. Whereas 17β-estradiol, estrone, and estrone-3-sulfate were detected in both tissues, estrone-3-glucuronide and 2-methoxy-estrone were detected predominately in GLT and ADT, respectively. Estrogen levels as well as ratios 17β-estradiol/estrone and estrone-3-sulfate/estrone differed significantly between GLT and ADT, yet less than between individuals. Furthermore, estrogen levels in GLT and ADT correlated significantly with each other. In contrast, levels of most transcripts encoding enzymes involved in biotransformation differed more than between individuals and did not correlate between ADT and GLT. Thus, mixed breast tissues (and plasma) will not provide meaningful information on local estrogen biotransformation (and interaction of compounds therewith) whereas relative changes in 17β-estradiol levels may be investigated in the more abundant ADT.

Keywords

Estradiol Biotransformation Tissue levels Breast adipose tissue Breast glandular tissue 

Notes

Acknowledgements

This work is part of the joint research project, IsoCross, entitled “Isoflavones: Cross-species comparison of metabolism, estrogen sensitivity, epigenetics and carcinogenesis”, which was supported in whole by the German Research Foundation to L. Lehmann (DFG LE 1329/10-1). The authors are indebted to Dr. Ulrike Waldhofen (mammoplasty specimen), Anne Scheffler (assistance during manuscript preparation), Ben Spielmann (help with sample collection, cryosection, microscopy and data administration), Sabine Winkler (help with analysis of estrogen conjugates), and Harald Schuchardt, Ersan Elemen, Thomas Kunz, Maryam Mahdiani (help with cryosection) as well as to Prof. Günter Vollmer (discussion of the manuscript).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

204_2019_2564_MOESM1_ESM.xlsx (27 kb)
Supplementary material 1 (XLSX 27 kb)
204_2019_2564_MOESM2_ESM.pdf (177 kb)
Supplementary material 2 (PDF 176 kb)
204_2019_2564_MOESM3_ESM.pdf (651 kb)
Supplementary material 3 (PDF 651 kb)
204_2019_2564_MOESM4_ESM.pdf (84 kb)
Supplementary material 4 (PDF 84 kb)
204_2019_2564_MOESM5_ESM.pdf (115 kb)
Supplementary material 5 (PDF 114 kb)

References

  1. Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23(2):83–89.  https://doi.org/10.1016/j.tem.2011.10.003 CrossRefGoogle Scholar
  2. Castagnetta LA, Granata OM, Traina A, Ravazzolo B, Amoroso M, Miele M, Bellavia V, Agostara B, Carruba G (2002) Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res 8:3146–3155Google Scholar
  3. Cavalieri E, Rogan E (2006) Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture. Ann N Y Acad Sci 1089:286–301.  https://doi.org/10.1196/annals.1386.042 CrossRefGoogle Scholar
  4. Depypere HT, Bolca S, Bracke M, Delanghe J, Comhaire F, Blondeel P (2015) The serum estradiol concentration is the main determinant of the estradiol concentration in normal breast tissue. Maturitas 81:42–45.  https://doi.org/10.1016/j.maturitas.2015.01.014 CrossRefGoogle Scholar
  5. Endogenous Hormones Breast Cancer Collaborative Group (2015) Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. Steroids 99:49–55.  https://doi.org/10.1016/j.steroids.2014.09.001 CrossRefGoogle Scholar
  6. Faupel-Badger JM, Fuhrman BJ, Xu X, Falk RT, Keefer LK, Veenstra TD, Hoover RN, Ziegler RG (2010) Comparison of liquid chromatography-tandem mass spectrometry, RIA, and ELISA methods for measurement of urinary estrogens. Cancer Epidemiol Biomarkers Prev 19:292–300.  https://doi.org/10.1158/1055-9965.EPI-09-0643 CrossRefGoogle Scholar
  7. Ferlay J, Colombet M, Bray F (2018) Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9. Lyon, France: International Agency for Research on Cancer. http://ci5.iarc.fr. Last accessed 08 April 2019
  8. Figueroa JD, Pfeiffer RM, Patel DA, Linville L, Brinton LA, Gierach GL, Yang XR, Papathomas D, Visscher D, Mies C, Degnim AC, Anderson WF, Hewitt S, Khodr ZG, Clare SE, Storniolo AM, Sherman ME (2014) Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology. J Natl Cancer Inst 106:dju286.  https://doi.org/10.1093/jnci/dju286 CrossRefGoogle Scholar
  9. Fleming JM, Miller TC, Quinones M, Xiao Z, Xu X, Meyer MJ, Ginsburg E, Veenstra TD, Vonderhaar BK (2010) The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo. BMC Med 8:27.  https://doi.org/10.1186/1741-7015-8-27 CrossRefGoogle Scholar
  10. Gaikwad NW, Rogan EG, Cavalieri EL (2007) Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 43:1289–1298.  https://doi.org/10.1016/j.freeradbiomed.2007.07.021 CrossRefGoogle Scholar
  11. Guillemette C, Belanger A, Lepine J (2004) Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview. Breast Cancer Res 6:246–254.  https://doi.org/10.1186/bcr936 CrossRefGoogle Scholar
  12. Hassiotou F, Geddes D (2013) Anatomy of the human mammary gland: Current status of knowledge. Clin Anat 26:29–48.  https://doi.org/10.1002/ca.22165 CrossRefGoogle Scholar
  13. Hu DG, Meech R, McKinnon RA, Mackenzie PI (2014) Transcriptional regulation of human UDP-glucuronosyltransferase genes. Drug Metab Rev 46:421–458.  https://doi.org/10.3109/03602532.2014.973037 CrossRefGoogle Scholar
  14. Hui Y, Yasuda S, Liu MY, Wu YY, Liu MC (2008) On the sulfation and methylation of catecholestrogens in human mammary epithelial cells and breast cancer cells. Biol Pharmaceut Bull 31:769–773CrossRefGoogle Scholar
  15. Labrie F (2015) All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol 145C:133–138.  https://doi.org/10.1016/j.jsbmb.2014.06.001 CrossRefGoogle Scholar
  16. Lee NA, Rusinek H, Weinreb J, Chandra R, Toth H, Singer C, Newstead G (1997) Fatty and fibroglandular tissue volumes in the breasts of women 20-83 years old: comparison of X-ray mammography and computer-assisted MR imaging. AJR Am J Roentgenol 168:501–506.  https://doi.org/10.2214/ajr.168.2.9016235 CrossRefGoogle Scholar
  17. Lehmann L, Jiang L, Wagner J (2008) Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells. Carcinogenesis 29(2):363–370.  https://doi.org/10.1093/carcin/bgm235 CrossRefGoogle Scholar
  18. Lepine J, Bernard O, Plante M, Tetu B, Pelletier G, Labrie F, Belanger A, Guillemette C (2004) Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab 89:5222–5232.  https://doi.org/10.1210/jc.2004-0331 CrossRefGoogle Scholar
  19. Liu ET (2000) Breast cancer research: where we are and where we should go. Breast Cancer Res 2:73–76CrossRefGoogle Scholar
  20. Lønning PE, Haynes BP, Straume AH et al (2011) Exploring breast cancer estrogen disposition: the basis for endocrine manipulation. Clin Cancer Res 17(15):4948–4958.  https://doi.org/10.1158/1078-0432.CCR-11-0043 CrossRefGoogle Scholar
  21. McNamara KM, Sasano H (2015) The intracrinology of breast cancer. J Steroid Biochem Mol Biol 145:172–178.  https://doi.org/10.1016/j.jsbmb.2014.04.004 CrossRefGoogle Scholar
  22. Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA (2015) The regulation of steroid action by sulfation and desulfation. Endocr Rev. 36:526–563.  https://doi.org/10.1210/er.2015-1036 CrossRefGoogle Scholar
  23. Nayeem F, Ju H, Brunder DG, Nagamani M, Anderson KE, Khamapirad T, Lu LJ (2014) Similarity of fibroglandular breast tissue content measured from magnetic resonance and mammographic images and by a mathematical algorithm. Int J Breast Cancer 2014:961679.  https://doi.org/10.1155/2014/961679 CrossRefGoogle Scholar
  24. Naz H, Islam A, Waheed A, Sly WS, Ahmad F, Hassan I (2013) Human beta-glucuronidase: structure, function, and application in enzyme replacement therapy. Rejuvenation Res 16:352–363.  https://doi.org/10.1089/rej.2013.1407 CrossRefGoogle Scholar
  25. Nickell WB, Skelton J (2005) Breast fat and fallacies: more than 100 years of anatomical fantasy. J Hum Lact 21:126–130.  https://doi.org/10.1177/0890334405276471 CrossRefGoogle Scholar
  26. Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME (2013) Challenges to the measurement of estradiol: an endocrine society position statement. J Clin Endocrinol Metab 98:1376–1387.  https://doi.org/10.1210/jc.2012-3780 CrossRefGoogle Scholar
  27. Runge-Morris M, Kocarek TA, Falany CN (2013) Regulation of the cytosolic sulfotransferases by nuclear receptors. Drug Metab Rev 45:15–33.  https://doi.org/10.3109/03602532.2012.748794 CrossRefGoogle Scholar
  28. Samavat H, Kurzer MS (2015) Estrogen metabolism and breast cancer. Cancer Lett 356:231–243.  https://doi.org/10.1016/j.canlet.2014.04.018 CrossRefGoogle Scholar
  29. Savolainen-Peltonen H, Vihma V, Leidenius M, Wang F, Turpeinen U, Hamalainen E, Tikkanen MJ, Mikkola TS (2014) Breast adipose tissue estrogen metabolism in postmenopausal women with or without breast cancer. J Clin Endocrinol Metab 99:2661–2667.  https://doi.org/10.1210/jc.2014-2550 CrossRefGoogle Scholar
  30. Sherman ME, Figueroa JD, Henry JE, Clare SE, Rufenbarger C, Storniolo AM (2012) The Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center: a unique resource for defining the “molecular histology” of the breast. Cancer Prev Res (Phila) 5:528–535.  https://doi.org/10.1158/1940-6207.CAPR-11-0234 CrossRefGoogle Scholar
  31. Stanczyk FZ, Mathews BW, Sherman ME (2015) Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: a critical appraisal of current science. Steroids 99(Pt A):91–102.  https://doi.org/10.1016/j.steroids.2014.12.011 CrossRefGoogle Scholar
  32. Thomas MP, Potter BV (2013) The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol 137:27–49.  https://doi.org/10.1016/j.jsbmb.2012.12.014 CrossRefGoogle Scholar
  33. Tralau T, Luch A (2013) The evolution of our understanding of endo-xenobiotic crosstalk and cytochrome P450 regulation and the therapeutic implications. Expert Opin Drug Metab Toxicol 9:1541–1554.  https://doi.org/10.1517/17425255.2013.828692 CrossRefGoogle Scholar
  34. Tsilidis KK, Allen NE, Key TJ, Dossus L, Lukanova A, Bakken K et al (2011) Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into cancer and nutrition. Br J Cancer 105:1436–1442.  https://doi.org/10.1038/bjc.2011.371 CrossRefGoogle Scholar
  35. Vihma V, Wang F, Savolainen-Peltonen H, Turpeinen U, Hamalainen E, Leidenius M, Mikkola TS, Tikkanen MJ (2016) Quantitative determination of estrone by liquid chromatography-tandem mass spectrometry in subcutaneous adipose tissue from the breast in postmenopausal women. J Steroid Biochem Mol Biol 155(Pt A):120–125.  https://doi.org/10.1016/j.jsbmb.2015.10.004 CrossRefGoogle Scholar
  36. Wang F, Vihma V, Badeau M, Savolainen-Peltonen H, Leidenius M, Mikkola T, Turpeinen U, Hamalainen E, Ikonen E, Wahala K, Fledelius C, Jauhiainen M, Tikkanen MJ (2012) Fatty acyl esterification and deesterification of 17 beta-estradiol in human breast subcutaneous adipose tissue. J Clin Endocrinol Metab 97:3349–3356.  https://doi.org/10.1210/jc.2012-1762 CrossRefGoogle Scholar
  37. Yager JD (2015) Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention—a review. Steroids 99:56–60.  https://doi.org/10.1016/j.steroids.2014.08.006 CrossRefGoogle Scholar
  38. Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282.  https://doi.org/10.1056/NEJMra050776 CrossRefGoogle Scholar
  39. Yaghjyan L, Colditz GA (2011) Estrogens in the breast tissue: a systematic review. Cancer Causes Control 22:529–540.  https://doi.org/10.1007/s10552-011-9729-4 CrossRefGoogle Scholar
  40. Zhang Y, Gaikwad NW, Olson K, Zahid M, Cavalieri EL, Rogan EG (2007) Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism 56:887–894.  https://doi.org/10.1016/j.metabol.2007.03.001 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Chair of Food Chemistry, Institute of Pharmacy and Food ChemistryUniversity of WürzburgWürzburgGermany
  2. 2.Chair of Mathematical Statistics with Applications in BiometricsTU Dortmund UniversityDortmundGermany
  3. 3.Clinic for Plastic and Aesthetic SurgeryWürzburgGermany
  4. 4.Department of Trauma, Hand, Plastic and Reconstructive SurgeryUniversity Hospital WürzburgWürzburgGermany

Personalised recommendations