title: AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis.
abstract: 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 bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more 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 upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers.
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: JuanJuan
authors: J
authors: Yin
authors: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors: Yen-Nien
authors: YN
authors: Liu
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Heather
authors: H
authors: Tillman
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Ben
authors: B
authors: Barrett
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Stephen
authors: S
authors: Hewitt
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Kris
authors: K
authors: Ylaya
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Lei
authors: L
authors: Fang
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Ross
authors: R
authors: Lake
authors: Department of Urology, University of Washington, Seattle, Washington.
authors: Eva
authors: E
authors: Corey
authors: Department of Urology, University of Washington, Seattle, Washington.
authors: Colm
authors: C
authors: Morrissey
authors: Department of Urology, University of Washington, Seattle, Washington.
authors: Robert
authors: R
authors: Vessella
authors: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. kellyka@mail.nih.gov.
authors: Kathleen
authors: K
authors: Kelly
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000074050:TWEAK Receptor; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse