Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model
Oh-Joon Kwon, … , Michael M. Ittmann, Li Xin
Oh-Joon Kwon, … , Michael M. Ittmann, Li Xin
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2626-2641. https://doi.org/10.1172/JCI84637.
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Research Article Oncology

Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model

Abstract

Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage–induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer.

Authors

Oh-Joon Kwon, Li Zhang, Jianghua Wang, Qingtai Su, Qin Feng, Xiang H.F. Zhang, Sendurai A. Mani, Robia Paulter, Chad J. Creighton, Michael M. Ittmann, Li Xin

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Figure 9

Notch promotes tumor metastasis by regulating FOXC2.

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Notch promotes tumor metastasis by regulating FOXC2. (A) Schematic illus...
(A) Schematic illustration of RBPJ binding sites in Foxc2 promoter. (B) ChIP assay for RBPJ and H3K27ac using the PB-Pten-NICD metastatic cell line. *P < 0.05 by Student’s t test. (C) Western blot analysis of phospho-P65 and FOXC2 in PB-Pten-NICD metastatic cell line with and without Bay11-7085 treatment. (D) qRT-PCR and Western blot analyses of PB-Pten-NICD metastatic cells infected with scrambled shRNA lentivirus, Foxc2 shRNA#1 lentivirus, and both. ***P < 0.001 by ANOVA Bonferroni post hoc test. (E) Growth curves of PB-Pten-NICD metastatic cells infected with scrambled shRNA lentivirus, Foxc2 shRNA#1 lentivirus, and both. No significant difference is detected among groups by 2-way ANOVA. (F) Transwell migration assay. Bar graphs show means ± SD of migrated cells per well from 3 independent experiments. *P < 0.05, ***P < 0.001 by ANOVA Bonferroni post hoc test. (G) NOD/SCID mice were inoculated with 2 × 106 cells each in individual groups via tail vein. Mice were imaged 5 weeks later. Bar graphs show means ± SD of bioluminescent signals. *P < 0.05 by ANOVA Bonferroni post hoc test.