title: Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis.
abstract: Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer. TBX2, a T-box family transcription factor that negatively regulates cell-cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here, we report that TBX2 is overexpressed in human prostate cancer specimens and bone metastases from xenograft mouse models of human prostate cancer. Blocking endogenous TBX2 expression in PC3 and ARCaPMprostate cancer cell models using a dominant-negative construct resulted in decreased tumor cell proliferation, colony formation, and invasionin vitroBlocking endogenous TBX2 in human prostate cancer mouse xenografts decreased invasion and abrogation of bone and soft tissue metastasis. Furthermore, blocking endogenous TBX2 in prostate cancer cells dramatically reduced bone-colonizing capability through reduced tumor cell growth and bone remodeling in an intratibial mouse model. TBX2 acted intransby promoting transcription of the canonical WNT (WNT3A) promoter. Genetically rescuing WNT3A levels in prostate cancer cells with endogenously blocked TBX2 partially restored the TBX2-induced prostate cancer metastatic capability in mice. Conversely, WNT3A-neutralizing antibodies or WNT antagonist SFRP-2 blocked TBX2-induced invasion. Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A, where WNT3A antagonists could be novel agents for the treatment of metastasis and for skeletal complications in prostate cancer patients.Cancer Res; 77(6); 1331-44. ©2017 AACR.
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Leland.Chung@cshs.org Srinivas.Nandana@cshs.org.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nandana
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Manisha
authors.initials: M
authors.lastname: Tripathi
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Duan
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Renjie
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Pathology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Bhowmick
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Leland.Chung@cshs.org Srinivas.Nandana@cshs.org.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein