Protein That Functions in Normal Breast May Also Contribute to Breast Cancer Metastasis

Paradox explored in a study reported in The American Journal of Pathology

Philadelphia, PA, February 16, 2012 – The trefoil factor 3 (TFF3) protein protects and maintains the integrity of the epithelial surface in the normal breast. New research has found that while TFF3 protein expression is higher in well-differentiated low grade tumors and therefore associated with features of a good prognosis, it has a more sinister role in breast cancer invasion and metastasis. The report is published in the March issue of The American Journal of Pathology

“Our findings suggest that TFF3 is regulated by estrogen and has beneficial properties in breast epithelia,” says lead investigator Felicity E.B. May, PhD, of the Northern Institute for Cancer Research and the Department of Pathology at Newcastle University, UK. “We propose that early during breast tumorigenesis, TFF3 retains its association with normal functionality of breast epithelial cells. Subsequently, with the loss of tumor cell differentiation, its function is subverted to promote the development of tumors and infiltration and lymph node metastasis.” 

To determine the role of TFF3 in breast cancer, researchers measured its level in tissue samples from normal breasts, benign breast lesions, in situ carcinomas, invasive carcinomas, and involved lymph nodes. TFF3 was expressed in the majority of benign and malignant breast lesions studied. Well-differentiated tumor types expressed higher levels of TFF3. There was a positive association between TFF3 protein expression and microvessel density, suggesting that it stimulates angiogenesis in breast tumors. 

A striking finding of the study is the strength and consistency of the association between TFF3 expression and a more metastatic phenotype in invasive breast cancer. TFF3 was expressed at higher levels in primary tumors with associated metastasis, and its expression was higher in malignant cells that have metastasized away from those within the primary tumor. There appears to be a switch in the normal polarized secretion of TFF3 in invasive cancer, which allows it to exert invasion-promoting effects. 

The study suggests that TFF3 may be one of the genes that mediate the various effects of estrogens in breast cancer. “The paradox remains, however, for both the estrogen receptor and TFF3, that they contribute to the normal physiology of the breast epithelium yet are involved in the progression of cancer,” notes Dr. May.

Importantly, the investigators also evaluated the potential of TFF3 as a biomarker of lymphovascular invasion and lymph node metastasis. They found that TFF3 had greater predictive power than other markers analyzed, including tumor grade, age, tumor size and type, and estrogen and progesterone receptor status. “Our study reinforces the view that TFF3 expression merits evaluation as a prognostic biomarker and as a predictive marker of response to therapy,” concludes Dr. May. “It is probable that its malign effects will be mitigated by adjuvant endocrine therapy in women with hormone-responsive cancers. However, the usefulness of TFF3 as a marker of hormone responsiveness needs to be evaluated.”

The article is “TFF3 Is a Normal Breast Epithelial Protein and Is Associated with Differentiated Phenotype in Early Breast Cancer but Predisposes to Invasion and Metastasis in Advanced Disease,” by A.R.H. Ahmed, A.B. Griffiths, M.T. Tilby, B.R. Westley, and F.E.B. May (doi: 10.1016/j.ajpath.2011.11.022). It will appear in The American Journal of Pathology, Volume 180, Issue 3 (March 2012) published by Elsevier.

# # #

Notes for editors
Full text of the article is available to credentialed journalists upon request; contact David Sampson at +1 215 239 3171 or ajpmedia@elsevier.com. Journalists wishing to interview the authors may contact Dr. Felicity May, at +44-191-246-4417; F.E.B.May@ncl.ac.uk.

About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology with an Impact Factor of 5.224 according to Thomson Reuters Journal Citation Reports® 2010.


About Elsevier

Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence, and ClinicalKey — and publishes nearly 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.

The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contact
David Sampson
Executive Publisher, Elsevier
+1 215 239 3171
ajpmedia@elsevier.com

Dr Audra E. Cox
Managing Editor, The American Journal of Pathology
+1 301 634 7409
acox@asip.org