Sporadic breast cancer, which is non-hereditary, turns out to be the most widespread, representing 85 to 90% of all cases, but remains the least well-known. Researchers at CNRS and CEA, working with a team from H pital Saint-Louis, have just discovered the cause of 50% of sporadic breast cancers. The results should also explain epidemiological studies which suggest that hormone treatment predisposes patients to breast cancer. The work is published in 'Cancer Research'. More than four out of five breast cancers are not related to hereditary factors. These cancers, which are called sporadic, are due to causes which were until recently considered complex and poorly understood. On the other hand, hereditary forms of cancer, which represent only 10 to 15% of breast cancers, have for years been the subjects of studies, work which has resulted in the identification of ten genes whose mutation increases the risk of cancer in an individual. Among these genes, nine are involved in the DNA damage response system, which is the collection of cell mechanisms that optimize the repair of DNA. The tenth gene codes for a protein which inhibits the action of the AKT1 enzyme. And among these ten genes, two are responsible for 50% of hereditary breast cancers: BRCA1 and BRCA2. Researchers from the "Radiobiologie mol?©culaire et cellulaire" (CNRS / CEA) lab took these data on hereditary cancers as the starting point for their research into non-hereditary forms. A link between hereditary and sporadic cancers It turns out that the AKT1 protein is over-expressed in 50% of sporadic breast cancers. Could this protein play a key role in predisposition to non hereditary breast cancer? The researchers, seeking an answer to this question, were able to show that activation of AKT1 leads to the sequestration of the BRCA1 protein in the cytoplasm. This makes it impossible for the protein to penetrate the nucleus, which prevents it from fulfilling its role in DNA repair. The cell then behaves as if it had no BRCA1 gene, without involving a mutation (unlike hereditary forms, where the BRCA1 gene undergoes an alteration). This phenomenon is observed in 50% of sporadic tumors. These results show a single, previously undetected, link between sporadic and hereditary cancers: the DNA damage response system. The researchers have also suggested that hormone treatment may confer upon patients a predisposition to breast cancer. As AKT1 is activated by hormones, hormone treatment could indeed, in some cases, result in the chronic activation of the molecule. If this is the case, it could lead to a deregulation of the BRCA1 gene, and, as a result, to breast cancer. These first results still need to be confirmed, something that the team led by Bernard Lopez will do soon through further laboratory and clinical studies. Institut de radiobiologie cellulaire et mol?©culaire, which is part of the Department of Life Sciences. The team is led by Fabien Calvo, director of Inserm unit 716 "Cibles pharmacologiques dans les cancers". cnrs.fr/

The workshop also heard how the overlap between cancer and cardiovascular disease was not of concern purely for research and development of new therapies, but also had practical considerations for immediate treatment now. "Many patients who receive chemotherapies develop heart failure symptoms, and the cardiologists have to interact with the oncology (cancer) specialists to make complex therapeutic decisions," said Trivella. So there is already interaction between the two groups out in the hospitals.

There has also been an overlap for some years in the imaging technologies that play a role in studying both types of disease in the laboratory. Positron electron tomography in particular has been used in both fields, producing images of the body region, such as a tumour, under study. "The Positron Electron Tomography Laboratory started years ago has been used to study the field of cardiac microcirculation and ischemic myocardial metabolism, and yet later on it also became a powerful tool in oncological diagnostic procedures," said Trivella.

There is also overlap between cardiovascular disease and cancer at the level of gene expression and regulation within cells, and in particular the role of small RNA molecules called micro RNAs. These molecules do not perform the role of RNA as traditionally understood in carrying genetic information from the DNA of genes to the protein factories called ribosomes. Instead they control the expression of genes themselves, and when this goes wrong, inflammatory processes can be triggered that in turn increase the risk of both cardiovascular diseases and cancers. "The future direction is to investigate whether and how the different gene networks regulated by micro RNAs are organized as a whole," said Giuseppe Rainaldi, the co-convenor of the workshop. "These studies will be necessary in order to understand complex biological processes and to approach micro RNA based therapy in a more efficient way."

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