ABSTRACT
The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2 mutant (BRCA2mt) patients are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 function in ovarian cancer. Transcriptomic and pathway analysis comparing BRCA1 mutant (BRCA1mt), BRCA2mt and homologous recombination wild-type (HRwt) ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type (BRCAwt), BRCA1null and BRCA2null mouse ovarian cancer cells, we observed preferential activation of the canonical Wnt/ß-catenin signaling in BRCAwt ovarian cancer cells while the non-canonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1null cells. Interestingly, BRCA2null mouse ovarian cancer cells, demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor, Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival.
ABSTRACT
In November 2023, a variety of disparate health organizations formed an international coalition to consolidate efforts and develop collaborative strategies in response to the increasing critical healthcare challenges caused by the recent war in Gaza. The coalition includes medical and public health experts, humanitarian practitioners, academics, and health policy-makers from across the world. Their membership has not much to do with mainstream humanitarian organisations. It is lead by the diaspora from the region. Their vision is the long-term reconstruction of the health system in Gaza while responding the most urgent needs. This collective effort will require explicit efforts to speak with one voice and avoid duplication. This collective movement may be an orginal initiative that may be able to beat the expected international donor fatigue.
