Fn14, a driver of invasive and metastatic behavior of breast tumors: a novel diagnostic, prognostic and therapeutic biomarker. In the last 10 years, breast cancer research has unveiled a new molecular classification for breast cancer which has begun to lead scientists to understand why breast tumors are so unpredictable in their response to therapy and why some breast tumors are much more aggressive than others.
This information is guiding new evidence-based treatment decisions, however, there is still a strong need to define and understand the molecular drivers and cellular mechanics of breast tumor cell invasion and metastasis, as these are the cellular processes we need to halt through optimal therapeutic intervention in order to save the lives of patients with progressive disease.
In 2008, the Cunliffe laboratory at TGen was the first to functionally validate that Fn14, a cell surface receptor that is overproduced in the majority of breast tumors, is sufficient by itself to regulate the invasive behavior of breast cancer cell lines in vitro. “Invasion” describes the process whereby tumor cells can move through healthy breast tissue away from the primary tumor site, access the lymphatic system and blood stream, spread to distant organs, and begin to grow as metastatic tumors, ultimately contributing to patient mortality. Invasive tumors have gained the ability to excrete tissue-digesting enzymes, and change their physical shape and adhesive properties in order to move through healthy breast tissue. Fn14 is a molecule that can drive these invasive processes in laboratory models of breast cancer. This work was published by Dr. Cunliffe in the scientific peer-reviewed journal Molecular Cancer Research (1).
The Cunliffe laboratory is now conducting functional validation studies to prove the pro-invasive and pro-metastatic behavior of Fn14 using well known mouse models of breast cancer metastasis. This work will be achieved by grafting human breast cancer cell lines into the mammary fat pad of a highly specialized breed of mice that will not reject grafted foreign tissue. The human breast cancer cell line that is to be used for this work overproduces Fn14, and is known to spontaneously metastasize to distant organs of the mouse in the same pattern as in humans. If the human breast cancer cells that have been specifically engineered by the Cunliffe laboratory to no longer produce Fn14, are not able to metastasize to distant mouse organs in a parallel series of mice, this will functionally validate Fn14 as a key driver of metastasis.
There is significant translational potential for Fn14 as a valuable novel diagnostic and predictive biomarker for patients who go on to develop advanced and treatment-resistant disease. While Fn14 is not expressed in normal mammary tissue, aberrant over-production of Fn14 in breast tumors has been shown to positively correlate with patients who have steroid hormone receptor-negative disease, positive lymph nodes, and metastases – all indicators of poor prognosis. In order to comprehensively evaluate the clinical utility of Fn14 as a diagnostic and prognostic biomarker in breast cancer, the Cunliffe laboratory is working to validate Fn14 expression in a series of early and advanced human breast tumors that have been annotated with corresponding patient outcome information including, development of metastasis, disease-free survival and overall survival.
Willis et al, Mol Cancer Res 2008;6(5):725–34