Molecular and Cellular Pathobiology AR-Regulated TWEAK-FN14 Pathway Promotes Prostate Cancer Bone Metastasis

The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bonemetastasis. In experimental models, depletion of FN14 inhibited bonemetastasis, and FN14 could be functionally reconstituted with IKKb-dependent, NFkB signaling activation. In human prostate cancer, upregulated FN14 expression was observed inmore than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstreammechanism, via FN14 signaling, through which the NFkB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers. Cancer Res; 74(16); 4306–17. 2014 AACR.