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Title: Role of trefoil proteins in breast cancer
Author: Ahmed, Ahmed Roshdi Hamed
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Trefoil proteins, TFF1, TFF2 and TFF3 are small molecular mass proteins that are secreted by mucus secreting epithelia. They share a three-looped structure, trefoil domain which contains six conserved cysteine residues that form three intramolecular disulphide bonds. TFF1 and TFF3 contain a seventh conserved uncoupled cysteine residue. In gastrointestinal mucosa, trefoil proteins are involved in stabilisation of the mucus layer, restitution of damaged mucosa and stimulation of epithelial cell motility. Increased expression of trefoil proteins has been reported in several human epithelial tumours and it has been proposed that trefoil proteins predispose to tumour cell migration, invasion and metastasis. Expression of trefoil genes is regulated by oestrogen in human breast cancer cell lines and strong association between expression of oestrogen receptor and expression of TFF1 and TFF3 mRNAs has been demonstrated in breast tumours. The role of trefoil proteins in breast cancer has not been fully understood. The purpose of this study is to investigate the molecular forms of TFF1 and TFF3 in breast cancer cells and to evaluate the expression of TFF1 and TFF3 in primary and metastatic breast tumours. The molecular forms of TFF1 and TFF3 proteins were examined in protein lysates and conditioned medium prepared from MCF-7, EFM-19 and EFF-3 breast cancer cell lines by western transfer analysis under non-reducing conditions and the different molecular forms were immunoprecipitated with anti-TFF1 and anti-TFF3 antibodies. Two distinct molecular forms of TFF1 and TFF3 were detected in breast cancer cell lines. They have approximate molecular masses of 66 kDa and 14.5 kDa for TFF1 and 66 kDa and 20 kDa for TFF3. The 66 kDa forms represent heterdimers that constitute one molecule of TFF1 or one molecule v of TFF3 bound to another protein of approximately 60 kDa through an intermolecular disulphide bond. The expression of TFF1 and TFF3 proteins was measured in 296 primary breast tumours and 76 metastatic deposits of breast tumours from patients who presented in the Newcastle Upon Tyne hospitals between 2002 and 2003 by immunohistochemistry. The association of TFF1 and TFF3 expression with various clinico-pathological features and with expression of oestrogen receptor, progesterone receptor, CD31, CD34, E-cadherin, Bcl-2 and Bax proteins was tested statistically with SPSS software (p<0.05). Clear TFF1 and TFF3 expression was demonstrated in normal, benign and malignant breast epithelial cells. There is no expression in stromal, endothelial or immune cells. There is a strong association between expression of TFF1 and expression of TFF3 in normal, benign and malignant breast epithelial cells. Expression of TFF1 and TFF3 varied enormously between tumour samples. Both had highest expression in mucinous and tubular breast carcinomas and both proteins are expressed at higher levels in lobular than in ductal breast cancers. Expression of TFF1 and TFF3 proteins is associated strongly with expression of both oestrogen and progesterone receptors. There is a negative association between TFF1 and TFF3 expression and tumour grade. There is however a positive association between TFF3 expression and presence of vascular invasion and presence of axillary lymph node metastasis and TFF3 expression is higher in metastatic breast tumour cells than in primary breast tumour cells. High expression of TFF3 is associated with increased number of small blood vessels, with increased expression of Bcl-2 and with increased expression of E-cadherin in primary breast cancer tissue. This is the first report about the expression of TFF3 and its association with expression of TFF1 in primary breast cancer tissues. The strong association between expression of TFF1 and TFF3 and expression of oestrogen receptor suggests that trefoil protein expression is dependent on oestrogen in a significant proportion of breast tumours. The high expression vi of TFF3 in breast tumours with vascular invasion and in metastatic breast tumour cells supports the hypothesis that TFF3 predisposes towards breast cancer cell invasion. The high molecular mass protein partner of TFF1 and TFF3 could be involved in mediation of trefoil proteins effects in breast cancer.
Supervisor: Not available Sponsor: Egyptian Government
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available