Human notch1 and pin1 unveil a molecular circuitry involved in tumorigenesis

Tiberi, Luca

Human notch1 and pin1 unveil a molecular circuitry involved in tumorigenesis

Tiberi, Luca

2008-04-01

http://hdl.handle.net/10077/2623

Doctoral Thesis

Contributor(s)

Rustighi, Alessandra

Abstract

Cancers arise as somatic cells mutate and escape the control of cell cycle, survival or death. These processes are normally regulated by several signalling pathways and recently several studies highlight the potential importance of the Notch1 signaling pathway in human cancer. Notch activation has been involved in several mouse models of mammary carcinogenesis and recently also in human breast cancer. Importantly loss of Numb, a negative regulator of Notch1, has been observed in about 50% of breast carcinomas (Pece et al., 2004). Expression of Notch1 and Ras correlates in breast carcinomas and expression of the Notch1 pathway ligand Jagged1 is a potential markers for breast cancer progression (Reedijk et al., 2005). Furthermore, the Notch1 interplay with pathways such as Wnt, c-Myc, is subverted in breast cancer, thus suggesting that Notch could be a target for drug-based therapy of breast cancer . Intriguingly also the prolyl-isomerase Pin1 is crucial in breast cancer and in several human malignancies through modulation of these pathways. Alterations of Pin1 have been implicated in the amplification of oncogenic signals, as demostarted by its cooperation with the Neu/Ras pathway in mammary tumorigenesis (Wulf et al., 2001) . The aim of this work was to unveil a possible role of Pin1 in the regulation of Notch1 pathway in breast cancer. Pin1 directly interacts with phosphorylated Notch1, and increases Notch1 cleavage by gamma-secretase. Accordingly, Pin1 contributes to Notch1 transforming properties in human breast cells. Notch1 in turn up-regulates Pin1, thus establishing a feed-forward loop that amplifies Notch1 signalling. Importantly human breast cancers bearing elevated levels of Pin1 have also deregulated expression of activated Notch1 and Hes-1 and these data underscore the relevance of our observations for human carcinogenesis.