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 July 1, 2016; First published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2626-2641. https://doi.org/10.1172/JCI84637.
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Categories: 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 1

Higher Notch signaling predicts poor clinical outcomes.

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Higher Notch signaling predicts poor clinical outcomes. (A) Expression h...
(A) Expression heat map of mRNA expression for major Notch signaling components in the Taylor data set of prostate cancer specimens (22). Notch signature score was generated by averaging of the normalized expression values of the genes shown. A gene signature of p53 transcriptional targets (http://p53.iarc.fr/TargetGenes.aspx) is inversely correlated with the Notch signature as shown. (B) Kaplan-Meier plots for correlations of Notch signature with prostate cancer recurrence in the Taylor data set (22) (left) and survival in the Sboner data set (23) (right). Log-rank test: P < 1 × 10–5. (C) Box plots show correlations of Notch signature with increasing Gleason grade, metastatic potential, and lethal outcome. P values are by t test. Box plots represent 5%, 25%, 75%, median, and 95%. (D) Scatter plot shows an inverse correlation between Notch signature and PTEN expression levels (Spearman’s correlation, r = –0.59, P < 1 × 10–10).