Options
A Pin1/mutant p53 axis promotes aggressiveness in breast cancer
Napoli, Marco
2011-04-28
Contributor(s)
Girardini, Javier
Abstract
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.
Publisher
Università degli studi di Trieste
Languages
en
File(s)