During my several years on the training grant, I have been studying the role of FGFR4 in prostate cancer. FGFR4 overexpression has been implicated in a variety of different cancers including breast, lung, and prostate among others. We sought to identify proteins which interact with FGFR4 in order to better understand how FGFR4 may be important for prostate cancer progression. In order to do this, I performed a yeast two-hybrid assay. This assay allows us to identify proteins which interact directly to FGFR4. One of proteins identified in this screen was IKKbeta. IKKbeta is an important protein in the NFkappaB signaling pathway, which is important for inflammation and has been implicated in the progression of cancer. NFkappaB is a transcription factor which is normally inhibited and held in the cytoplasm by IkappaB. IKKbeta is activated by phosphorylation on serine residues. Once activated, IKKbeta then phosphorlyates IkappaB and targets it for degredation. This releases NFkappaB to move to the nucleus and leads to transcription of a variety of genes, many of which are important for inflammation and anti-apoptosis.

We have been characterizing the interaction between IKKbeta and FGFR4 and trying to determine the importance of this interaction. We have discovered the novel finding that FGFR4 kinase activity and interaction with IKKbeta actually leads to a decrease in NFkappaB signaling, which would implicate FGFR4 as a tumor suppressor. This finding goes against the most current thinking on the role of FGFR4 in cancer progression. It is possible that FGFR4 is overexpressed in cells to inhibit NFkappaB activity, and cancers arise when mutations develop in FGFR4 and alter the receptor's kinase activity. Our novel findings are important for prostate cancer research as we have discovered a potential target for cancer treatment. Treating cells with FGF to activate FGFR4 may indeed lead to a decrease in NFkappaB-induced cancer progression. Without support from the Growth Regulation & Oncogenesis Training Grant program, this research would not have been possible and I am thankful for the opportunity to work toward understanding the complex signaling cascade that leads to prostate cancer progression.

PUBLICATIONS (resulting from this training)

Drafahl, K. A., C. W. McAndrew, D. J. Donoghue (2009) Signaling from fibroblast growth factor receptors in development and disease. In "Handbook of Cell Signaling", Second Edition (R. Bradshaw & E. Dennis, Eds.) Oxford:Academic Press, pp. 1939-1948.

Kristine A. Drafahl, April N. Meyer, Christopher W. McCandrew, Daniel J. Donoghue. The novel interaction of FGFR4 and IKKbeta negatively regulates NF-kappaB activity. Manuscript in revision.

Drafahl, Kristine A., Donoghue, Daniel J. FGFR2 as a Mediator of Opposing Forces: Bringing Balance to Inflammatory Signaling in Breast Cancer. (Manuscript in preparation.- Invited review to Cancer Research)