Breast cancer, the leading cause of death among women in France, is the most commonly occurring cancer in women. 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 (1), working with a team from Hôpital Saint-Louis (2), 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 moléculaire 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 (3) 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 (4) will do soon through further laboratory and clinical studies.

(1) Institut de radiobiologie cellulaire et moléculaire, which is part of the Department of Life Sciences.
(2) The team is led by Fabien Calvo, director of Inserm unit 716 "Cibles pharmacologiques dans les cancers"
(3) Like for example estrogen treatment.
(4) CNRS senior researcher and deputy director at the laboratory "Radiobiologie moléculaire et cellulaire"

This research program has received the Ligue contre le cancer Label.

Article: AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51. Isabelle Plo, Corentin Laulier, Fabienne Lebrun, Laurent Gauthier, Fabien Calvo et Bernard Lopez. Cancer Research. 15 November 2008.