- A Pin1/mutant p53 axis promotes aggressiveness in breast cancer
- Napoli, Marco
Subject
- mutant p53 gain of function
- prolyl isomerase Pin1
- breast cancer
- SCUOLA DI DOTTORATO DI RICERCA IN BIOMEDICINA MOLECOLARE
- BIO/13 BIOLOGIA APPLICATA
Description
- 2009/2010
- Mutations in the TP53 gene are among the most frequent genetic alterations in human cancers. As a consequence of these mutations p53 loses its tumour suppressor functions and may acquire novel oncogenic activities (gain of function) sustaining tumour formation and progression. Many in vivo studies highlighted that mutant p53 gain of function is associated with elevated protein levels, supporting the notion that in tumour cells altered signalling could stabilize and activate mutant p53, with mechanisms similar to those required to stimulate wild-type p53. The aim of my PhD work was to investigate the mechanisms underlying mutant p53 gain of function, focusing on factors that might link cancer-related signalling with mutant p53 activity. An intriguing candidate for this role is the phosphorylationdependent prolyl isomerase Pin1, that transduces phosphorylation signalling into conformational changes affecting the functions of its substrates, as ours and other laboratories have reported for wild-type p53. Despite Pin1 supports wild-type p53 functions, Pin1 is frequently overexpressed in human tumours and has been shown to promote both Her2/Neu/Ras and Notch1 dependent transformation. So we reasoned that the physiological role of Pin1 as a component of checkpoint mechanisms might be subverted during tumourigenesis, thereby turning it into an essential partner of mutant p53 and a critical amplifier of its oncogenic functions. Indeed, we now demonstrate that Pin1 enhances tumourigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent cell transformation. In human breast cancer cells, Pin1 promotes both mutant p53 dependent inhibition of the anti-metastatic factor p63 and the induction of a mutant p53 transcriptional program to increase tumor aggressiveness. Accordingly, we have identified a transcriptional signature (the Pin1/mutant p53 signature) that is associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 over-expression influences the prognostic value of p53 mutation. Considering that TP53 mutation is more frequent in tumors with higher risk of recurrence such as triple-negative cases and that some of the Pin1/mutant p53 signature genes are over-expressed in triple negative breast cancers, our findings carry therapeutic implications for this kind of cancers and possibly also for other tumours bearing mutant p53 and high levels of Pin1.
- XXII Ciclo
- 1983
Date
- 2011-05-19T13:49:17Z
- 2012-04-29T04:01:24Z
- 2011-04-28
Type
- Doctoral Thesis
Format
- application/pdf
Identifier
urn:nbn:it:units-9093