Elevated levels of TFF3 in endometrial cancer patients

Authors: D. Neubert 1;  D. Ondrová 1;  J. Hambálek 1;  M. Maděrka 1 ;  K. Sobková 1;  D. Stejskal 2,3;  G. Krejčí 3;  R. Pilka 1
Authors‘ workplace: Porodnicko-gynekologická klinika FN a LF UP, Olomouc, přednosta prof. MUDr. R. Pilka, Ph. D. 1;  VIA Agel, ředitelka Mgr. Ing. K. Murtingerová 2;  Oddělení laboratorní medicíny Středomoravské nemocniční, Prostějov, přednosta prof. MUDr. D. Stejskal, Ph. D. 3
Published in: Ceska Gynekol 2018; 83(2): 109-114


Trefoil peptides are a family of small proteins that are expressed in a site-specific fashion by certain epithelial tissues. These peptides might be used as markers for neoplastic uterine disease.

Experimental study.

Department of Obstetrics and Gynaecology, University Hospital, Medical Faculty, Palacký University, Olomouc; Department of Laboratory Biochemistry, Central Moravian Hospital Trust, Member of Agel holding, Prostějov.

During the time period from 2012 to 2015 eighty-nine women underwent hysteroscopy and endometrial biopsy for postmenopausal bleeding. Fifty three patients, at the age of (mean ± standard deviation) 63,4 ± 9,5 (33–80) years were diagnosed with endometrial cancer, six patients at the age of 62,9 ± 6,4 (55–74) years were diagnosed with endometrial hyperplasia and thirty patients at the age of 63,3 ± 9,3 (48–62) years diagnosed with endometrial atrophy represented control group. At the day of surgery the venous blood was sampled and subsequently examined for the levels of TFF1, TFF2 and TFF3.

TFF3 levels were significantly higher in patients with endometrial carcinoma but not in endometrial hyperplasia subgroup. The levels of TFF1 and TFF2 were not different in selected histopathological subgroups.

We have shown elevated levels of TFF3 but not of TFF1 and TFF2 in patients with endometrial cancer. TFF1, TFF2 and TFF3 levels were not elevated in patients with endometrial hyperplasia.

TFF, carcinoma, endometrial, trefoil factor, serous


1. Bignotti, E., Ravaggi, A., Tassi, RA., et al. Trefoil factor 3: a novel serum marker identified by gene expression profiling in high-grade endometrial carcinomas. Br J Cancer 2008, 99(5), p. 768–773.

2. Bonkhoff, H., Stein, U., Welter, C., et al. Differential expression of the pS2 protein in the human prostate and prostate cancer: association with premalignant changes and neuroendocrine differentiation. Hum Pathol, 1995, 26(8), p. 824–828.

3. Borthwick, JM., Charnock-Jones, DS., Tom, BD., et al. Determination of the transcript profile of human endometrium. Mol Hum Reprod, 2003, 9(1), p. 19–33.

4. Cappelletti, V., Coradini, D., Scanziani, E., et al. Prognostic relevance of pS2 status in association with steroid receptor status and proliferative activity in node-negative breast cancer. Eur J Cancer, 1992, 28A(8–9), p. 1315–1318.

5. Foekens, JA., Rio, MC., Seguin, P., et al. Prediction of relapse and survival in breast cancer patients by pS2 protein status. Cancer Res, 1990, 50(13), p. 3832–3827.

6. Fox, JG., Rogers, AB., Whary, MT., et al. Accelerated progression of gastritis to dysplasia in the pyloric antrum of TFF2 -/- C57BL6 x Sv129 Helicobacter pylori-infected mice. Am J Pathol, 2007, 171(5), p. 1520–1528.

7. Hanby, AM., Poulsom, R., Elia, G., et al. The expression of the trefoil peptides pS2 and human spasmolytic polypeptide (hSP) in ‚gastric metaplasia‘ of the proximal duodenum: implica­tions for the nature of ‚gastric metaplasia‘. J Pathol, 1993, 169(3), p. 355–360.

8. Hanby, AM., Poulsom, R., Singh, S., et al. Spasmolytic polypeptide is a major antral peptide: distribution of the trefoil peptides human spasmolytic polypeptide and pS2 in the stomach. Gastroenterology, 1993, 105(4), p. 1110–1116.

9. Hauser, F., Poulsom, R., Chinery, R., et al. hP1.B, a human P-domain peptide homologous with rat intestinal trefoil factor, is expressed also in the ulcer-associated cell lineage and the uterus. Proc Natl Acad Sci U S A, 1993, 90(15), p. 6961–6965.

10. Henry, JA., Bennett, MK., Piggott, NH., et al. Expression of the pNR-2/pS2 protein in diverse human epithelial tumours. Br J Cancer, 1991, 64(4), p. 677–682.

11. Higashiyama, M., Doi, O., Kodama, K., et al. Estimation of serum level of pS2 protein in patients with lung adenocarcinoma. Anticancer Res, 1996, 16(4B), p. 2351–2355.

12. Ishibashi, Y., Ohtsu, H., Ikemura, M., et al. Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer. Sci Rep, 2017, 7(1), p. 4846.

13. Jorgensen, KH., Thim, L., Jacobsen, HE. Pancreatic spasmolytic polypeptide (PSP): I. Preparation and initial chemical characterization of a new polypeptide from porcine pancreas. Regul Pept, 1982, 3(3–4), p. 207–219.

14. Kao, LC., Tulac, S., Lobo, S., et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology, 2002, 143(6), p. 2119–2138.

15. Masiakowski, P., Breathnach, R., Bloch, J., et al. Cloning of cDNA sequences of hormone-regulated genes from the MCF-7 human breast cancer cell line. Nucleic Acids Res 1982, 10(24), p. 7895–7903.

16. Maxwell, GL., Chandramouli, GV., Dainty, L., et al. Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer. Clin Cancer Res, 2005, 11(11), p. 4056–4066.

17. May, FE., Westley, BR. Expression of human intestinal trefoil factor in malignant cells and its regulation by oestrogen in breast cancer cells. J Pathol, 1997, 182(4), p. 404–413.

18. Mhawech, P., Benz, A., Cerato, C., et al. Downregulation of 14–3–3 sigma in ovary, prostate and endometrial carcinomas is associated with CpG island methylation. Mod Pathol, 2005, 18(3), p. 340–348.

19. Mickova, I., Pilka, R., L‘ubusky, M., et al. [Molecular prognostic factors and pathogenesis of endometrial cancer]. Ces Gynekol, 2006, 71(4), p. 355–360.

20. Mika, O., Koznarova, J., Sak, P. [Ultrasound staging of stage I–II endometrial cancer, analysis of own file in the years 2012–2016]. Ces Gynekol, 2017, 82(3), p. 218–226.

21. Neubert, D., Pilka, R., Stejskal, D., et al. [The role of trefoil factor family in gynecological disease]. Ces Gynekol, 81(6), p. 444–450.

22. Pallud, C., Le Doussal, V., Pichon, MF., et al. Immunohistochemistry of pS2 in normal human breast and in various histological forms of breast tumours. Histopathology, 1993, 23(3), p. 249–256.

23. Piggott, NH., Henry, JA., May, FE., et al. Antipeptide antibodies against the pNR-2 oestrogen-regulated protein of human breast cancer cells and detection of pNR-2 expression in normal tissues by immunohistochemistry. J Pathol, 1991, 163(2), p. 95–104.

24. Playford, RJ., Marchbank, T., Chinery, R., et al. Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration. Gastroenterology, 1995, 108(1), p. 108–116.

25. Podolsky, DK., Lynch-Devaney, K., Stow, JL., et al. Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J Biol Chem, 1993, 268(9), p. 6694–6702.

26. Poulsen, SS., Thulesen, J., Christensen, L., et al. Metabolism of oral trefoil factor 2 (TFF2) and the effect of oral and parenteral TFF2 on gastric and duodenal ulcer healing in the rat. Gut, 1999, 45(4), p. 516–522.

27. Poulsom, R., Hanby, AM., Lalani, EN., et al. Intestinal trefoil factor (TFF 3) and pS2 (TFF 1), but not spasmolytic polypeptide (TFF 2) mRNAs are co-expressed in normal, hyperplastic, and neo­plastic human breast epithelium. J Pathol, 1997, 183(1), p. 30–38.

28. Probst, JC., Zetzsche, T., Weber, M., et al. Human intestinal trefoil factor is expressed in human hypothalamus and pituitary: evidence for a novel neuropeptide. FASEB J, 1996, 10(13), p. 1518–1523.

29. Rio, MC., Bellocq, JP., Daniel, JY., et al. Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa. Science, 1988, 241(4866), p. 705–708.

30. Risinger, JI., Maxwell, GL., Chandramouli, GV., et al. Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res 2003, 63(1), p. 6–11.

31. Semple, JI., Newton, JL., Westley, BR., et al. Dramatic diurnal variation in the concentration of the human trefoil peptide TFF2 in gastric juice. Gut, 2001, 48(5), p. 648–655.

32. Slama, J., Kocian, R. [Technique of pelvic and paraaortic lympha­denectomy]. Ces Gynekol, 81(4), p. 253–264.

33. Suemori, S., Lynch-Devaney, K., Podolsky, DK. Identification and characterization of rat intestinal trefoil factor: tissue- and cell-specific member of the trefoil protein family. Proc Natl Acad Sci U S A, 1991, 88(24), p. 11017–11021.

34. Thim, L. A new family of growth factor-like peptides. ‚Trefoil‘ disulphide loop structures as a common feature in breast cancer associated peptide (pS2), pancreatic spasmolytic polypeptide (PSP), and frog skin peptides (spasmolysins). FEBS Lett, 1989, 250(1), p. 85–90.

35. Tomasetto, C., Rio, MC., Gautier, C., et al. hSP, the domain-duplicated homolog of pS2 protein, is co-expressed with pS2 in stomach but not in breast carcinoma. EMBO J, 1990, 9(2), p. 407–414.

36. Vestergaard, EM., Poulsen, SS., Gronbaek, H., et al. Development and evaluation of an ELISA for human trefoil factor 3. Clin Chem, 2002, 48(10), p. 1689–1695.

37. Weinberger, V., Minar, L., Felsinger, M., et al. [Postoperative administration of octreotide to reduce lymphorrhea, lymphocele, lymphedema and lymphatic ascites after lymphadenectomy in gynecological malignancies]. Ces Gynekol, 2017, 82(2), p. 92–99.

38. Yamaguchi, J., Mino-Kenudson, M., Liss, AS., et al. loss of trefoil factor 2 from pancreatic duct glands promotes formation of intraductal papillary mucinous neoplasms in mice. Gastroenterology 2016, 151(6), p. 1232–1244 e10.

Paediatric gynaecology Gynaecology and obstetrics Neonatology Paediatrics Reproduction medicine
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account