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Gene Review

TFF1  -  trefoil factor 1

Homo sapiens

Synonyms: BCEI, Breast cancer estrogen-inducible protein, D21S21, HP1.A, HPS2, ...
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Disease relevance of TFF1


Psychiatry related information on TFF1

  • Mutations in genes encoding presenilins (PS1 and PS2) cosegregate with the majority of early onset cases of familial Alzheimer's disease [4].
  • From the results of the present study we can conclude that i) a significant interaction between Cath-D and pS2 was found in this case series; ii) the prognostic relationship should not be underestimated in clinical decision making; iii) a predictive score obtained considering the contribution of PgR, pS2 and Cath-D could be useful for clinical use [5].

High impact information on TFF1

  • Consistent with a repressive role for PADI4, this enzyme is recruited to the pS2 promoter following hormone induction when the gene is transcriptionally downregulated [6].
  • This modification appears on the estrogen-regulated pS2 promoter when the CARM1 methyltransferase is recruited during transcriptional activation [6].
  • We provide here a comprehensive picture of events resulting in transcriptional activation of a gene, through evaluating the estrogen receptor-alpha (NR3A1) target pS2 gene promoter in MCF-7 cells [7].
  • Moreover, transcription of the resident estrogen-induced pS2 gene was partially inhibited by exposing MCF-7 cells to progestins or glucocorticoids [8].
  • Deletion of the N-terminal domain (region A/B) has no effect on activation of a reporter gene containing a vitellogenin estrogen-responsive element (ERE) and the HSV-tk promoter, whereas it severely impairs activation of the human pS2 gene promoter [9].

Chemical compound and disease context of TFF1


Biological context of TFF1


Anatomical context of TFF1


Associations of TFF1 with chemical compounds


Physical interactions of TFF1

  • The trefoil protein TFF1 is bound to MUC5AC in human gastric mucosa [23].
  • Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia [24].
  • Furthermore, partial digestion of the A2 and pS2 ERE-bound ER with chymotrypsin or trypsin produced distinct protease cleavage patterns [25].

Enzymatic interactions of TFF1

  • The highest pS2 protein level observed in ER-negative unfavorable subgroups (15 ng/mg) was considered as the cut-off value which defined estrogen-regulated expression of pS2 protein [26].
  • It was shown that the full-length PS-2 protein is phosphorylated constitutively within its N-terminal domain by casein kinases, whereas the PS-1 protein is not [27].

Regulatory relationships of TFF1

  • TFF2 is co-expressed with TFF1 in gastric surface epithelial cells, but its potential role in vivo is unclear [22].
  • TFF3 was expressed in the ampulla of Vater. mRNA expression of TFF1 was detected in only approximately 25% of the investigated samples [28].
  • Transcription factor GATA-6 activates expression of gastroprotective trefoil genes TFF1 and TFF2 [29].
  • Our results indicate that local EGF/URO secretion induces pS2 and hSP in adjacent cells, and that these molecules are then available to participate in pathophysiological responses [30].
  • The interference of toxaphene with the ER mediated responses was supported by a significant suppression of endogenously expressed pS2 RNA and decreased levels of secreted pS2 protein [31].

Other interactions of TFF1

  • Relatively large amounts of TFF3-but not TFF1 and TFF2-are present in the posterior lobe of the human pituitary, where it is probably released into the bloodstream [32].
  • The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3 [33].
  • TFF3 mRNA localized patchily throughout the UACL, whereas TFF1 mRNA was found in the upper portions of the lineage and TFF2 mRNA and its product in the acini [34].
  • Of 20 ductal adenocarcinomas, TFF1 and EGFR were moderately or strongly expressed in 16 and 12, respectively [35].
  • All hyperplastic polyps displayed immunoreactivity for TFF1, MUC5AC, and MUC1 in more than 75 per cent of the cells [36].

Analytical, diagnostic and therapeutic context of TFF1


  1. Helicobacter pylori interacts with the human single-domain trefoil protein TFF1. Clyne, M., Dillon, P., Daly, S., O'Kennedy, R., May, F.E., Westley, B.R., Drumm, B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. High expression of the trefoil protein TFF1 in interval breast cancers. Crosier, M., Scott, D., Wilson, R.G., Griffiths, C.D., May, F.E., Westley, B.R. Am. J. Pathol. (2001) [Pubmed]
  3. Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells. Rodrigues, S., Rodrigue, C.M., Attoub, S., Fl??jou, J.F., Bruyneel, E., Bracke, M., Emami, S., Gespach, C. Oncogene (2006) [Pubmed]
  4. Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing. Saura, C.A., Tomita, T., Davenport, F., Harris, C.L., Iwatsubo, T., Thinakaran, G. J. Biol. Chem. (1999) [Pubmed]
  5. Impact of steroid receptors, pS2 and cathepsin D on the outcome of N+ postmenopausal breast cancer patients treated with tamoxifen. Dittadi, R., Biganzoli, E., Boracchi, P., Salbe, C., Mione, R., Gatti, C., Gion, M. Int. J. Biol. Markers (1998) [Pubmed]
  6. Histone deimination antagonizes arginine methylation. Cuthbert, G.L., Daujat, S., Snowden, A.W., Erdjument-Bromage, H., Hagiwara, T., Yamada, M., Schneider, R., Gregory, P.D., Tempst, P., Bannister, A.J., Kouzarides, T. Cell (2004) [Pubmed]
  7. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Métivier, R., Penot, G., Hübner, M.R., Reid, G., Brand, H., Kos, M., Gannon, F. Cell (2003) [Pubmed]
  8. Steroid hormone receptors compete for factors that mediate their enhancer function. Meyer, M.E., Gronemeyer, H., Turcotte, B., Bocquel, M.T., Tasset, D., Chambon, P. Cell (1989) [Pubmed]
  9. Functional domains of the human estrogen receptor. Kumar, V., Green, S., Stack, G., Berry, M., Jin, J.R., Chambon, P. Cell (1987) [Pubmed]
  10. Primary mucinous carcinomas of the skin express TFF1, TFF3, estrogen receptor, and progesterone receptors. Hanby, A.M., McKee, P., Jeffery, M., Grayson, W., Dublin, E., Poulsom, R., Maguire, B. Am. J. Surg. Pathol. (1998) [Pubmed]
  11. The gene encoding the human spasmolytic protein (SML1/hSP) is in 21q 22.3, physically linked to the homologous breast cancer marker gene BCEI/pS2. Tomasetto, C., Rockel, N., Mattei, M.G., Fujita, R., Rio, M.C. Genomics (1992) [Pubmed]
  12. Prognostic value of PS2 and cathepsin D in 710 human primary breast tumors: multivariate analysis. Foekens, J.A., van Putten, W.L., Portengen, H., de Koning, H.Y., Thirion, B., Alexieva-Figusch, J., Klijn, J.G. J. Clin. Oncol. (1993) [Pubmed]
  13. The regulation of growth and protein expression by estrogen in vitro: a study of 8 human ovarian carcinoma cell lines. Langdon, S.P., Hirst, G.L., Miller, E.P., Hawkins, R.A., Tesdale, A.L., Smyth, J.F., Miller, W.R. J. Steroid Biochem. Mol. Biol. (1994) [Pubmed]
  14. Chromatin modification of the trefoil factor 1 gene in human breast cancer cells by the Ras/mitogen-activated protein kinase pathway. Espino, P.S., Li, L., He, S., Yu, J., Davie, J.R. Cancer Res. (2006) [Pubmed]
  15. Ulcer associated cell lineage glands expressing trefoil peptide genes are induced by chronic ulceration in ileal pouch mucosa. Pera, M., Heppell, J., Poulsom, R., Teixeira, F.V., Williams, J. Gut (2001) [Pubmed]
  16. The human trefoil peptide, TFF1, is present in different molecular forms that are intimately associated with mucus in normal stomach. Newton, J.L., Allen, A., Westley, B.R., May, F.E. Gut (2000) [Pubmed]
  17. Tumour necrosis factor alpha and nuclear factor kappaB inhibit transcription of human TFF3 encoding a gastrointestinal healing peptide. Loncar, M.B., Al-azzeh, E.D., Sommer, P.S., Marinovic, M., Schmehl, K., Kruschewski, M., Blin, N., Stohwasser, R., Gött, P., Kayademir, T. Gut (2003) [Pubmed]
  18. The pathogenesis of duodenal gastric metaplasia: the role of local goblet cell transformation. Shaoul, R., Marcon, P., Okada, Y., Cutz, E., Forstner, G. Gut (2000) [Pubmed]
  19. Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. Leung, W.K., Yu, J., Chan, F.K., To, K.F., Chan, M.W., Ebert, M.P., Ng, E.K., Chung, S.C., Malfertheiner, P., Sung, J.J. J. Pathol. (2002) [Pubmed]
  20. TFF peptides in the human efferent tear ducts. Paulsen, F.P., Hinz, M., Schaudig, U., Thale, A.B., Hoffmann, W. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  21. Trefoil factors TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. Hoffmann, W. Cell. Mol. Life Sci. (2005) [Pubmed]
  22. Trefoil factor-2, human spasmolytic polypeptide, promotes branching morphogenesis in MCF-7 cells. Lalani, E.N., Williams, R., Jayaram, Y., Gilbert, C., Chaudhary, K.S., Siu, L.S., Koumarianou, A., Playford, R., Stamp, G.W. Lab. Invest. (1999) [Pubmed]
  23. The trefoil protein TFF1 is bound to MUC5AC in human gastric mucosa. Ruchaud-Sparagano, M.H., Westley, B.R., May, F.E. Cell. Mol. Life Sci. (2004) [Pubmed]
  24. Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal adenocarcinomas. McChesney, P.A., Aiyar, S.E., Lee, O.J., Zaika, A., Moskaluk, C., Li, R., El-Rifai, W. Cancer Res. (2006) [Pubmed]
  25. Estrogen response elements function as allosteric modulators of estrogen receptor conformation. Wood, J.R., Greene, G.L., Nardulli, A.M. Mol. Cell. Biol. (1998) [Pubmed]
  26. PS2 protein in breast carcinomas: cut-off value of estrogen-regulated expression. Nikolić-Vukosavljević, D., Grujić-Adanja, G., Janković, R., Nesković-Konstantinović, Z., Branković-Magić, M. Neoplasma (2001) [Pubmed]
  27. Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Walter, J., Grünberg, J., Capell, A., Pesold, B., Schindzielorz, A., Citron, M., Mendla, K., George-Hyslop, P.S., Multhaup, G., Selkoe, D.J., Haass, C. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  28. Trefoil factor family (TFF) peptides of normal human Vater's ampulla. Paulsen, F., Varoga, D., Paulsen, A., Tsokos, M. Cell Tissue Res. (2005) [Pubmed]
  29. Transcription factor GATA-6 activates expression of gastroprotective trefoil genes TFF1 and TFF2. Al-azzeh, E.D., Fegert, P., Blin, N., Gött, P. Biochim. Biophys. Acta (2000) [Pubmed]
  30. Epidermal growth factor (EGF/URO) induces expression of regulatory peptides in damaged human gastrointestinal tissues. Wright, N.A., Poulsom, R., Stamp, G.W., Hall, P.A., Jeffery, R.E., Longcroft, J.M., Rio, M.C., Tomasetto, C., Chambon, P. J. Pathol. (1990) [Pubmed]
  31. Effect of toxaphene on estrogen receptor functions in human breast cancer cells. Bonefeld Jørgensen, E.C., Autrup, H., Hansen, J.C. Carcinogenesis (1997) [Pubmed]
  32. Co-localization of TFF3 peptide and oxytocin in the human hypothalamus. Jagla, W., Wiede, A., Dietzmann, K., Rutkowski, K., Hoffmann, W. FASEB J. (2000) [Pubmed]
  33. Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions. Yeh, T.S., Tseng, J.H., Chen, T.C., Liu, N.J., Chiu, C.T., Jan, Y.Y., Chen, M.F. Hepatology (2005) [Pubmed]
  34. Duodenal content reflux esophagitis in the rat: an animal model for the ulcer-associated cell lineage (UACL)? Hanby, A.M., Pera, M., Filipe, I., Duranceau, A., Wright, N.A., Pera, M., Grande, L., Poulsom, R. Am. J. Pathol. (1997) [Pubmed]
  35. Characterisation of oestrogen receptor, progesterone receptor, trefoil factor 1, and epidermal growth factor and its receptor in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma. Yeh, T.S., Jan, Y.Y., Chiu, C.T., Ho, Y.B., Chen, T.C., Lee, K.F., Chan, K.M., Hsu, J.C., Hwang, T.L., Chen, M.F. Gut (2002) [Pubmed]
  36. Patterns of expression of trefoil peptides and mucins in gastric polyps with and without malignant transformation. Nogueira, A.M., Machado, J.C., Carneiro, F., Reis, C.A., Gött, P., Sobrinho-Simões, M. J. Pathol. (1999) [Pubmed]
  37. Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone. Jackerott, M., Lee, Y.C., M??llg??rd, K., Kofod, H., Jensen, J., Rohleder, S., Neubauer, N., Gaarn, L.W., Lykke, J., Dodge, R., Dalgaard, L.T., S??strup, B., Jensen, D.B., Thim, L., Nex??, E., Thams, P., Bisgaard, H.C., Nielsen, J.H. Endocrinology (2006) [Pubmed]
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