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
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
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.
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
Details on the publication
Advanced on-line publication: 23 March 2014, Nature Cell
Original title: "Metabolic control of YAP/TAZ by the
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