Objectif
"Mutations of BRCA1 tumor suppressor gene account for 5-10% of hereditary breast cancers. Clinically, BRCA1-mutated cancers represent a unique subtype, with distinctive risk factors and poor prognosis. High-throughput technologies have identified genomic and transcriptomic signatures that are shared by sporadic and BRCA1-mutated breast tumors. BRCA1 mutations have been implicated in other types of tumors such as gastric, pancreatic and prostate cancers. A more detailed picture of BRCA1 tumor suppression functions is needed to design better tailored therapies for these aggressive cancers.
BRCA1-mutated tumors tend to accumulate mutations in PTEN and p53 tumor suppressor genes. The current model of BRCA1-related tumorigenesis posits that in BRCA1 mutation carries, the cell of origin bearing BRCA1 mutation at heterozygote status, undergoes loss of BRCA1 wild-type allele and loss or mutation of PTEN and p53 tumor suppressors. Although this intriguing model lacks in vivo evidence, it is widely accepted that PTEN and p53 gene inactivation are required for survival and transformation of BRCA1-mutated cells.
BRCA1, PTEN and p53 have been implicated in the regulation of intracellular levels of reactive oxygen species (ROS). Redox homeostasis derives from an imbalance between ROS generation and elimination. Redox homeostasis is crucial in the maintenance of cellular functions and it has implications in tumor development and sensitivity to anti-cancer therapies.
This study will investigate the role of PTEN and p53-regulated pathways in affecting the redox homeostasis of BRCA1 null cells. The activity of Nrf2 and FoxO transcription factors that regulate ROS and are related to BRCA1, PTEN and p53 will be considered. These signalling pathways will be analyzed in normal mouse mammary gland and in human breast cancers. Results will be translated into pre-clinical settings through orthoxenografts of primary human tumor samples and in vivo administration of chemotherapeutics."
Champ scientifique
Appel à propositions
FP7-PEOPLE-2013-IIF
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Régime de financement
MC-IIF - International Incoming Fellowships (IIF)Coordinateur
08908 L'HOSPITALET DEL LLOBREGAT
Espagne