Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model
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
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
View: Text | PDF
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

×

Figure 2

Notch signaling is dispensable for initiation and progression of prostate cancer in the Pten-null model.

Options: View larger image (or click on image) Download as PowerPoint
Notch signaling is dispensable for initiation and progression of prostat...
(A) Bar graph shows means ± SD of prostate weight of 1-year-old PB-Pten and PB-Pten-Rbpj mice. n = 3 per group. No significant difference is noted between the 2 groups (Student’s t test). (B) H&E staining of anterior (AP), dorsolateral (DLP), and ventral (VP) prostate tissues from 1-year-old PB-Pten and PB-Pten-Rbpj mice. (C–E) Coimmunostaining of K5 and K8, P63, and AR (C); Ki-67 and K8 (D); and cleaved caspase 3 (CC3) and K8 (E) of prostate tissues from 1-year-old PB-Pten and PB-Pten-Rbpj mice. Scale bars: 50 μm.