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An Italian study discovered how cancer and the metabolic processes responsible for the formation of cholesterol become allies in breast cancer 

Anti-cholesterol drugs can help stop breast cancer. Here is why

24.03.2014 -

The link between cholesterol and cancer is not new. Extensive evidence over the last several years has highlighted numerous aspects of a link, which remains to be fully investigated, between tumours and this molecule, and not only when it is present in excessive levels in the bloodstream. In addition to intake through diet, cholesterol, which is not always a dangerous foe, is also produced by our own cells, which need it to build their membranes. If necessary, our cells are able to launch a series of chemical reactions which, through various steps and intermediate by-products, are eventually able to synthesize cholesterol.


In cancer, these processes are often subverted and hijacked to the tumour's advantage. Until today, however, how this happened was unclear. The discovery was made by a team of scientists headed by Giannino Del Sal, ordinary professor of applied biology at the University of Trieste and head of the molecular oncology unit of the CIB National Laboratory based at Area Science Park in Trieste.


In the paper published online today by the authoritative scientific journal Nature Cell Biology the Italian researchers showed for the first time how the metabolic pathway that produces cholesterol is the hub where the destinies and the actions of certain key actors in tumour transformation and in the propensity of breast tumours to lead to metastasis and resistance to chemotherapy come together: the YAP/TAZ factors.


Certain substances produced in the intermediate steps of this process are used not only to synthesize cholesterol, but also in processes that make YAP/TAZ always active and uninhibited.  Pushing a cell to produce cholesterol thus also means pushing it to accelerate these powerful factors. What pushes breast tumour cells in this direction is another notorious cancer ally, the mutant p53 protein, one of the main accelerators of malignant transformation and progression.


«By discovering this association» states Del Sal, who coordinated this study and is also the director of the Department of Life Sciences of the University of Trieste «we have come full circle - and paved the way for new research - by linking, through the metabolic cholesterol pathway, two of the main molecular pathways that cause the most aggressive behaviours of various forms of cancer».


The researchers managed to discover and link all this starting from afar. «Over the last few years we realized that YAP/TAZ are targets that are crucial to strike in the fight against cancer - explains one of the paper's authors, Stefano Piccolo, ordinary professor of molecular biology at the University of Padua - but reaching them is not easy». The team's strategy can be summed up as 'finding new mechanisms to use old drugs'. This approach provides one major advantage: «If an old drug can be used for new purposes, the time it takes for it to be approved for patient use can be shortened dramatically. On the basis of this idea, we tested molecules already approved for use in humans in order to find out which of these drugs were also active in blocking or inhibiting the action of YAP/TAZ in breast cancer cells». The most effective of the one hundred or so therapeutic agents tested turned out to be statins, the well-known drugs used to lower cholesterols. The researchers built upon this finding by looking into the biological details and molecular aspects of this action.


From a clinical point of view, this is a major discovery.  «Although we already have some evidence on the possible cancer-fighting role of statins, we now have, for the first time, a solid biological basis to expect that statins - or other drugs that can strike the metabolic pathway that brings about the synthesizing of cholesterol - can effectively fight breast tumours, especially the most aggressive forms. On this basis, we will be able to accurately design clinical trials to confirm this».


This discovery is one of the achievements of the team coordinated by Del Sal in which AIRC, the Italian Association for Cancer Research invested in 2010 through its special funding programme for clinical molecular oncology financed by the 5X1000 tax donation programme in Italy.


A brief overview of the study

What are YAP/TAZ?
These are very similar molecules that can guide the transcription of other genes and thus drive cell behaviour. YAP and TAZ help organs grow during embryonic development, and in routine tissue renewal and regeneration in adults.
In tumours, YAP and TAZ escape the rigid controls they are normally subjected to, and re-programme cells, making them more malignant and better able to form metastases.


What is mutant p53?
p53 is a protein that normally plays a crucial role: safeguarding the integrity of our genetic cell heritage, and preventing our genome from accumulating mutations - dangerous alterations that can induce cells to undergo malignant transformation. In tumours, p53 is often lost and can frequently be found in a mutant form. From a good guardian, mutant p53 turns into a dangerous accelerator of tumour transformation and progression.

The discovery

In breast tumours, YAP and TAZ are regulated by the cholesterol metabolism, which in turn is regulated by mutant p53.


What do statins do?
By blocking the metabolic pathway (also known as the mevalonate pathway) which leads to the synthesis of cholesterol, but also of a series of intermediate products, one can stop the production of those molecules required by YAP/TAZ to remain active. YAP/TAZ are thus inactivated and degraded, and the tumour loses some of its most powerful determinants, and is easier to extirpate in this weakened state.


Details on the publication
Advanced on-line publication: 23 March 2014, Nature Cell Biology
Original title: "Metabolic control of YAP/TAZ by the mevalonate pathway".
Authors: Giovanni Sorrentino, Naomi Ruggeri, Valeria Specchia, Michelangelo Cordenonsi, MiguelMano, Sirio Dupont, Andrea Manfrin, Eleonora Ingallina, Roberta Sommaggio, Silvano Piazza, Antonio Rosato, Stefano Piccolo, Giannino Del Sal