Notch Regulates the Stem Cell Activities of Prostate Basal Cells in Coordination with Tgfβ

The Notch pathway is evolutionarily conserved and its deregulation has been observed in cancer of almost every tissue including the prostate. However, the role of Notch in prostate carcinogenesis remains controversial. To understand the functions that go askew in cancer we wanted to determine the purpose of Notch in the prostate. We used a prostate epithelial loss of function transgenic mouse to study Notch. Surprisingly, we found that canonical Notch activity is dispensable for the maintenance of homeostasis.

However, we challenged the prostate with rapid changes in proliferation and differentiation by castration and hormone replacement. Following regeneration we observed more primitive and proliferative basal cells. Furthermore, using an in vitro prostate sphere assay, we recapitulated these findings showing that attenuation of Notch signaling enhances proliferation and inhibits differentiation of prostate basal cells.

Interestingly, quiescence in the prostate has also been found to be regulated by Tgfβ signaling. We show here that Notch signaling lies downstream of Tgfβ and is essential for the up-regulation of CDKIs to arrest the cell cycle. Furthermore, we demonstrate that Notch activity is able to regulate expression of multiple members of the Tgfβ pathway. These findings reveal a key positive feedback loop between the Notch and Tgfβ pathways that enforces a cytostatic program.

This raises important considerations for the treatment of prostate and epithelial cancer. The functional link between Tgfβ and Notch must be studied in the context of cancer to determine if loss of this interaction is a requirement in the progression of carcinogenesis.