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FCT (Foundation for Science and Technology), Ministry for Science, Technology and Higher Education of Portugal

Breast cancer is the most common malignancy in women, with 1 in 9 of all British and American women developing this disease in their lifetimes. Chemotherapy with anthracyclines, particularly with epirubicin, play a key role in the medical management of breast cancer, but the molecular pathways underlying response and resistance to chemotherapy are not fully understood. The transcription factor forkhead box M1 (FOXM1) has been implicated in various genotoxic drug resistance however its exact role and mechanism of action remain unclear. My work demonstrates that the inhibition of FOXM1 renders MCF‑7 epirubicin resistant breast cancer cells (MCF-7 EpiR) more susceptible to DNA double‑strand breaks (DSBs) induced by epirubicin. Conversely, the ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. In fact, I found that FOXM1 is required for homologous recombination (HR) DSB repair pathway. I also identified the BRCA1-interacting protein 1 (BRIP1) as a direct transcription target of FOXM1 by promoter analysis and chromatin immunoprecipitation (ChIP) assay. Remarkably, the requirement of FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1. Moreover, like FOXM1, BRIP1 depletion is also able to resensitize MCF-7 EpiR cells to epirubicin treatment, suggesting that FOXM1 regulates BRIP1 expression to modulate epirubicin‑induced DNA damage repair and drug resistance. Additionally, I identified BRCA1 as an upstream regulator of FOXM1 expression via FOXA1. By means of overexpression and knockdowns I demonstrated that both BRCA1 and FOXA1 regulate FOXM1 expression at the protein and mRNA levels in MCF‑7 cells. Furthermore, I showed that although BRCA1 is able to transactivate FOXM1 promoter, this activation is enhanced by the introduction of FOXA1, indicating that BRCA1 and FOXA1 synergistically activate FOXM1. In agreement, clinical data identifies higher FOXA1 methylation in BRCA1 tumors and show an inverse correlation between FOXA1 methylation and FOXA1 expression, suggesting that the BRCA1-mediated suppression of FOXA1 methylation increases FOXA1 expression levels which in turn enable FOXM1 transcriptional activation and therefore protection against DNA damage. Such roles of FOXM1 make it an attractive target for drug intervention and a prognostic marker for predicting and monitoring response to epirubicin.
Título cortoSFRH/BD/47191/2008
EstadoFinalizado
Fecha de inicio / finalización efectiva1/01/0931/12/12