A Pin/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer
Javier E.Girardini et al. Cancer Cell 20, 79-91, July 12, 2011
Presenter: Pei-Yi Chou
Date/Time: 2011/10/20, 16:00-17:00
Commentator: Dr. Li-Wha Wu
Location: Room 601, Med College Building
Abstract
Background: Mutation in tumor suppressor gene TP53 is the most common genetic alterations in human cancers.
Mutant p53 has dominant-negative effects. It forms aberrant protein complex interfering the activity of interacting
partners, such as the antimetastatic factor p63, thus contributing to malignant phenotypes. Oncogenic stress
signaling could activate mutant p53 through mechanisms similar to those required to stimulate wild-type p53. Pin1
is a critical regulator of wild-type p53 activities in cells exposed to genotoxic stress. Pin1 is a WW domain-containing
prolyl isomerase that transduces phophorylation signaling into conformational changes affecting the functions of its
substrates. Pin1 overexpression is often found in human tumors, and Pin1 has been shown to promote both
Her2/Neu/Ras and Notch1 dependent transformation of breast cells.
Objectives: To investigate whether Pin1 triggers mutant p53 activity and the underlying mechanisms.
Results: Mice lacking Pin1 displayed an increased median tumor-free survival in both p53M/+ and p53M/M mice.
p53M/MPin1+/+ MEF cells form more colonies in soft agar as compared with p53M/MPin1-/-. Also, Pin1 promoted
MDA-MB-231 cell migration, and knockdown of mutant p53 abolished Pin1-promoted cell migration. Modified form
of endogenous mutant p53, p53K280-4M, which is unable to bind Pin1, could not increase cell migration under
Pin1 overexpression. When Pin1 was overexpressed, binding of p53 with p63 was increased as determined by CoIP.
When Pin1 was overexpressed, the transcription function of p63 was inhibited as revealing by the reduced
expression of p63 targeted CCNG2 and Sharp-1. In control, knockdown of p53 increased their expressions.
Overexpression of Pin1 also increased the transcription of CCNA2, a known direct target gene of the mutant
p53-NF-Y complex. Moreover, several genes were identified to be downregulated by depletion of either Pin1 or
mutant p53. Kaplan-Meier survival analysis showed that patients expressing high levels of these genes displayed a
shorter time to distant metastasis (TDM) and a reduced overall survival (OS). Silencing those genes suppressed cell
migration.
Conclusion: Pin1 activates mutant p53 gain of function. Pin1 overexpression enhances mutant p53-dependent cell
migration in part by inhibition of the metastasis suppressor p63. This phenotype requires the phosphorylation of
S46 and S315 in mutant p53. In addition, Pin1/mutant p53 axis activates several gene transcription; therefore
contributing to the malignant phenotypes. Patient with high Pin1 expression and mutant p53 in tumors display
lower overall survival compared to low Pin1 expression and mutant p53, or wild-type p53 in tumors. Therefore, high
Pin1 and mutant p53 together could be a prognostic index for cancer paitents.
References:
Adorno, M., M. Cordenonsi, et al. (2009). "A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced
metastasis." Cell 137(1): 87-98.