12.07.2011 -

Two characteristics in particular make breast tumours especially aggressive: the presence of mutations in malignant cells that transform factor p53 into a dangerous tumour promoter and the expression at abnormal levels of a specific protein, enzyme Pin1.

 

It is already known that in cancerous cells, mutated p53 dramatically influences tumour progression.  Now however, a new and vital piece of the puzzle has been added to the complex mosaic that is breast cancer: mutated p53 and Pin1 together form a lethal combination that subverts cell functions.

 

The molecular trait resulting from the combination of these two elements is associated with a total hijacking of the genetic programme active within the cells, which leads to the expression of a specific group of genes that allow tumour cells to acquire aggressive characteristics and the ability to migrate and invade other tissues. These are the essential factors responsible for the cancer cell's journey outwards from the original organ, leading to metastases that invade other organs.

 

The discovery, arising from a study conducted by the international research team headed by Giannino Del Sal, Full Professor of Cell Biology at the Faculty of Medicine, University of Trieste and Head of the Molecular Oncology Unit at the CIB National Laboratory at Trieste Area Science Park, is of particular clinical relevance. Indeed, expert analyses carried out on over 200 breast cancer cases have shown that in breast tumours, the presence of excessive levels of Pin1 combined with the presence of factor p53 gene mutations are linked to poor disease outcome.

 

Objective: more efficient prognoses for specific new treatments

 

"A critical aspect at the time of disease classification," states Del Sal, "is the identification, through specific biomarkers, of those cases with a high risk of recurrence and the ability to predict patient response to treatments, a fundamental requirement that will allow the improvement of treatment strategies and help guide treatment decisions. Our work provides a significant contribution in this very area."

 

The researcher explains, "Mutations in the gene that encode the p53 protein are alterations that frequently occur in women with a breast tumour. Most of these alterations have not in fact resulted in the destruction of the protein, but have instead converted it into a powerful tumour promoter. In characterising the disease we often rely on tests that reveal this type of aberration.

 

However, what clearly emerges from our studies, is that in order to get a detailed picture of the aggressiveness of the tumour and the progression of the disease, it is important to combine the analysis of the Pin1 protein levels with this research study.

 

A prognostic method of this type, which is based on the identification of the state of p53 mutation and the amount of Pin1 in tumour cells, would discriminate better, between the various cases of breast carcinoma, those with a lower probability of survival and those that have an ineffective response to treatment, particularly to a certain type of adjuvant chemotherapy. To understand which patients exhibit these characteristics and why it is crucial to design new strategies to combat tumours."

 

According to Del Sal, it is not only through mutated p53 and Pin1 that important information on the disease could be obtained, but also from the evaluation of the gene expression that makes up the molecular signature associated with the action of these two proteins.

 

From the entire genetic programme activated in cancerous cells by mutated p53 and Pin1, a group of 10 genes can be extracted and, if used as indicators, such genes reveal important aspects of tumour development.

 

Their expression is in fact linked to the clinical outcome of the disease: using a data base comprising over 800 breast cancer cases, researchers found that in patients expressing higher than average levels of these genes, the time interval between diagnosis of the primary tumour and diagnosis of metastasis in other parts of the body was shorter, and survival was reduced.

 

 

Breast cancer in women is not only the most frequently diagnosed form of cancer but is also the leading cause of death from cancer. It is estimated that each year over one million women worldwide are diagnosed with breast cancer.

 

Over the years, progress made in diagnosis, prevention programmes and the development of new treatment strategies has resulted in a marked decrease in mortality. Nevertheless, too many women continue to die each year as a result of the disease.

 

A strong heterogeneity characterises this and other types of tumour and does not only relate to the different types of cells that make up the breast tissue but also, for example, to the differential response of patients to therapeutic treatments. The complexity of this tumour is not associated with a full understanding of its biology.

 

The tools currently available in clinical practice, albeit valid, do not fully grasp this heterogeneity and do not always allow an accurate prognosis to be made nor a determination of the likelihood of treatment success, essential factors when deciding on the treatment solution to be adopted and, where necessary, promoting the development of new intervention strategies.

 

The discovery made by Del Sal and his colleagues, in this respect represents an important advance in understanding the complex nature of breast carcinoma and at the same time provides potential new tools for carrying out highly efficient and targeted prognostic analyses for the development of specific and innovative treatments.

 

"Furthermore," concludes Del Sal, "its value is not limited to breast tumours alone. Tumours that have the same type of gene mutations for factor p53, may in fact reveal features similar to those found in breast carcinomas. In this event, the clinical implications of the discovery could be greater, and even in other tumours the mutated Pin1/p53 molecular axis could turn out to be associated with the progression of the disease and provide interesting treatment targets."

 

This study was conducted thanks mainly to funding received from the Italian Association for Cancer Research (AIRC - Associazione Italiana per la Ricerca sul Cancro), the Friuli Venezia Giulia Region and the European Community.

 

p53 and Pin1, together for better or for worse

It has been known for some time that the protein p53, once mutated, is transformed from the "master guardian" of the genetic integrity of the cell into an extremely dangerous catalyst of malignant transformation and of the process that leads to the formation of metastases. What was not known until now is that, apart from the changes that lead mutated factor p53 to take  on a new and disturbing identity, this molecular "Mr Hyde" needs an "accomplice", to fully express its potential as a tumour promoter within the cell dynamics.

 

Even less known, was the fact that the very protein Pin1, the ally thanks to which normal p53 is able to fulfil its important task as a tumour suppressor, was the perfect partner for the dangerous mutated p53.

 

Pin1, like the two-faced Janus, with one side towards the vital suppression of malignant transformation and the other towards the powerful tumour promoter, is an enzyme that, in response to specific signals, causes a change in the structure of the proteins with which it interacts, leading to the end of the modulation of the protein functions.

 

What the research work headed by Giannino Del Sal, and published in the journal Cancer Cell, now brings to light, is an almost indissoluble relationship between Pin1 and p53, whether normal or mutated, without which the factor, for better in the normal cell or for worse in the tumour cell, is unable to fully carry out its functions. Indeed the authors of the study have used a variety of approaches to demonstrate the dependence of mutated p53 on Pin1 in terms of carrying out its functions: in its absence, it is as if the mutated p53 were crippled.

 

Together, the two proteins open the way to a genetic programme that is decisive for tumour aggression and crucial from a clinical standpoint.