Summary
Background
The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA present in MCF-7 breast cancer cells. The objective of this work was to evaluate the cytosolic TFF1 content in breast carcinomas, its possible relationship with different clinical–pathological parameters, and its potential prognostic significance and predictive value.
Methods
Cytosolic TFF1 levels were examined by immunoradiometric assay in 1031 patients with invasive breast cancer. The median follow-up period was of 50 months.
Results
There was a wide variability of cytosolic TFF1 levels in tumors (0.9–743.2 ng/mg protein). Statistical analysis showed that TFF1 levels were significantly higher in premenopausal patients (p=0.001), as well as in tumors showing any of the following characteristics: good differentiation (p=0.0001), ER and PgR positivity (p=0.0001 and p=0.001, respectively), diploidy (p=0.045) and a high S-phase fraction (p=0.001). In addition, the presence of high intratumoral TFF1 levels (cut-off: 2 ng/mg protein) was independently associated with a shorter overall survival in the group of patients as a whole (p=0.001) as well as in the subgroup with node-negative breast cancer (p=0.0004). Likewise, high intratumoral TFF1 levels were associated with a more prolonged overall survival in patients who received adjuvant tamoxifen (p=0.004).
Conclusions
In breast cancer patients, intratumoral TFF1 levels are associated with a better clinical outcome, especially in those with node-negative tumors. In addition, TFF1 levels have a low but significant predictive value in regards to response to adjuvant therapy with tamoxifen.
Similar content being viewed by others
References
Wong WM, Poulsom R, Wright NA, 1999 Trefoil peptides Gut 44:890–895
Luqmani Y, Bennett C, Paterson I, Corbishley CM, Rio MC, Chambon P, Ryall G, 1989 Expression of the pS2 gene in normal, benign and neoplastic human stomach Int J Cancer 44:806–812
Hahnel E, Robbins P, Hahnel R, 1993 Expression of the pS2 gene in normal breast tissue. Breast Cancer Res Treat 28:295–297
Jakowlew SB, Breathnach R, Jeltsch JM, Masiakowski P, Chambon P, 1984 Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7 Nucleic Acids Res 12:2861–2878
Rio MC, Chambon P, 1990 The pS2 gene, mRNA, and protein: a potential marker for human breast cancer Cancer Cells 2:269–274
Gion M, Mione R, Pappagallo GL, Gatti C, Nascimben O, Bari M, Leon AE, Vinante O, Bruscagnin G, 1993 PS2 in breast cancer–alternative or complementary tool to steroid receptor status? Evaluation of 446 cases Br J Cancer 68:374–379
Besse G, Kwiatkowski F, Gaillard G, Daver A, Dalifard I, Basuyau JP, Brunelle P, Wafflart J, Angibeau RM, Auvray E, 1994 [PS2 as a prognostic factor in 1065 cases of human breast cancer. A multicenter study] Bull Cancer 81:289–296
Soubeyran I, Wafflart J, Bonichon F, de Mascarel I, Trojani M, Durand M, Avril A, Coindre JM, 1995 Immunohistochemical determination of pS2 in invasive breast carcinomas: a study on 942 cases Breast Cancer Res Treat 34:119–128
Foekens JA, van Putten WL, Portengen H, de Koning HY, Thirion B, Alexieva-Figusch J, Klijn JG, 1993 Prognostic value of PS2 and cathepsin D in 710 human primary breast tumors: multivariate analysis J Clin Oncol 11:899–908
Soubeyran I, Quenel N, Coindre JM, Bonichon F, Durand M, Wafflart J, Mauriac L, 1996 pS2 protein: a marker improving prediction of response to neoadjuvant tamoxifen in post-menopausal breast cancer patients Br J Cancer 74:1120–1125
Elledge RM, Green S, Pugh R, Allred DC, Clark GM, Hill J, Ravdin P, Martino S, Osborne CK, 2000 Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study Int J Cancer 89:111–117
Altman DG, Lausen B, Sauerbrei W, Schumacher M, 1994 Dangers of using “optimal” cutpoints in the evaluation of prognostic factors J Natl Cancer Inst 86:829–835
Ioakim-Liossi A, Karakitsos P, Aroni K, Markopoulos C, Delivelioti K, Gogas J, Kyrkou K, 1997 DNA ploidy and pS2 protein expression in breast cancer Cytopathology 8:171–176
Inaji H, Koyama H, Motomura K, Noguchi S, 1996 Differential distribution of ErbB-2 and pS2 proteins in ductal carcinoma in situ of the breast Breast Cancer Res Treat 37:89–92
Nichols PH, Ibrahim NB, Padfield CJ, Cawthorn SJ, 1995 Correlation of pS2 expression of involved lymph nodes in relation to primary breast carcinoma Eur J Surg Oncol 21:151–154
Pujol P, Daures JP, Brouillet JP, Maudelonde T, Rochefort H, Grenier J, 1999 Time at surgery during menstrual cycle and menopause affects pS2 but not cathepsin D levels in breast cancer Br J Cancer 79:909–914
Reshkin SJ, Tedone T, Correale M, Mangia A, Casavola V, Paradiso A, 1999 Association of pS2 (TFF1) release with breast tumour proliferative rate: in vitro and in vivo studies Cell Prolif 32:107–118
Harding C, Osundeko O, Tetlow L, Faragher EB, Howell A, Bundred NJ, 2000 Hormonally regulated proteins in breast secretions are markers of target organ sensitivity Br J Cancer 82:354–360
Luqmani YA, Ricketts D, Ryall G, Turnbull L, Law M, Coombes RC, 1993 Prediction of response to endocrine therapy in breast cancer using immunocytochemical assays for pS2, oestrogen receptor and progesterone receptor Int J Cancer 54:619–623
Robbins PD, Hahnel E, Sterrett GF, Harvey J, Carrello S, Hahnel R, 1993 Expression of the pS2 gene in breast cancer – a comparison of pS2 protein radioimmunoassay and immunohistochemistry Pathology 25:255–260
Spyratos F, Andrieu C, Hacene K, Chambon P, Rio MC, 1994 pS2 and response to adjuvant hormone therapy in primary breast cancer Br J Cancer 69:394–397
Lefebvre O, Chenard MP, Masson R, Linares J, Dierich A, LeMeur M, Wendling C, Tomasetto C, Chambon P, Rio MC, 1996 Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein Science 274:259–262
Calnan DP, Westley BR, May FE, Floyd DN, Marchbank T, Playford RJ, 1999 The trefoil peptide TFF1 inhibits the growth of the human gastric adenocarcinoma cell line AGS J Pathol 188:312–317
Bossenmeyer-Pourie C, Kannan R, Ribieras S, Wendling C, Stoll I, Thim L, Tomasetto C, Rio MC, 2002 The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis J Cell Biol 157:761–770
Williams R, Stamp GW, Gilbert C, Pignatelli M, Lalani EN, 1996 pS2 transfection of murine adenocarcinoma cell line 410.4 enhances dispersed growth pattern in a 3-D collagen gel J Cell Sci 109( Pt 1):63–71
Prest SJ, May FE, Westley BR, 2002 The estrogen-regulated protein, TFF1, stimulates migration of human breast cancer cells Faseb J 16:592–594
Brown AM, Jeltsch JM, Roberts M, Chambon P, 1984 Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7 Proc Natl Acad Sci USA 81:6344–6348
Crosier M, Scott D, Wilson RG, Griffiths CD, May FE, Westley BR, 2001 High expression of the trefoil protein TFF1 in interval breast cancers Am J Pathol 159:215–221
Martin V, Ribieras S, Song-Wang XG, Lasne Y, Frappart L, Rio MC, Dante R, 1997 Involvement of DNA methylation in the control of the expression of an estrogen-induced breast-cancer-associated protein (pS2) in human breast cancers J Cell Biochem 65:95–106
Nunez AM, Berry M, Imler JL, Chambon P, 1989 The 5’ flanking region of the pS2 gene contains a complex enhancer region responsive to oestrogens, epidermal growth factor, a tumour promoter (TPA), the c-Ha-ras oncoprotein and the c-jun protein Embo J 8:823–829
Acknowledgement
Supported by grants from ISCIII, Red de Centros de Cáncer RTICCC (C03/10) and Obra Social Cajastur.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Corte, M., Tamargo, F., Alvarez, A. et al. Cytosolic levels of TFF1/pS2 in breast cancer: their relationship with clinical–pathological parameters and their prognostic significance. Breast Cancer Res Treat 96, 63–72 (2006). https://doi.org/10.1007/s10549-005-9041-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-005-9041-7