American Association for Cancer Research
00085472can160497-sup-162499_2_supp_3752708_4h0v24.pptx (207.77 kB)

Supplementary figure 1 from Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2–WNT Signaling Axis

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posted on 2023-03-31, 01:03 authored by Srinivas Nandana, Manisha Tripathi, Peng Duan, Chia-Yi Chu, Rajeev Mishra, Chunyan Liu, Renjie Jin, Hironobu Yamashita, Majd Zayzafoon, Neil A. Bhowmick, Haiyen E. Zhau, Robert J. Matusik, Leland W.K. Chung

Plot showing relative protein expression of TBX2 and WNT3A in human PCa cell lines




Department of Defense Prostate Cancer Research Program



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 ARCaPM prostate cancer cell models using a dominant-negative construct resulted in decreased tumor cell proliferation, colony formation, and invasion in vitro. Blocking 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 in trans by 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.