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.