TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer.

Felicity E B May,Bruce R Westley

doi:10.1530/erc-15-0129

Abstract

The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis.

Highlights

Many of the 1.7 million women diagnosed each year with breast cancer benefit from endocrine therapy (May 2014)
TFF1 and TFF3 mRNAs were induced by oestrogen in five oestrogenresponsive but not in two oestrogen-nonresponsive breast cancer cell lines
TFF3 protein was not detected in the oestrogen-unresponsive MDA-MB-231 cells or in T-47D cells, which expressed low levels of TFF3 mRNA

Summary

Introduction

Many of the 1.7 million women diagnosed each year with breast cancer benefit from endocrine therapy (May 2014). Introduced originally for the treatment of breast cancer patients who present or relapse following surgery with metastatic disease, endocrine therapy remains a mainstay of systemic intervention (Beatson 1896, Ariazi et al 2006). Two main categories of drugs target the dependence of malignant breast epithelial cells upon oestrogens. Antioestrogens are competitive inhibitors of oestrogens for the oestrogen receptor, which is a ligand-dependent transcription factor with many target genes (May & Westley 1988, Wright et al 2009). Tamoxifen and raloxifene have partial agonist activity (Powles 2013), whereas antioestrogens, such as fulvestrant, are pure antagonists (Howell et al 2005, Johnston & Cheung 2010)

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