RESUMEN
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 patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/ß-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null 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 BRCA2-null 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. SIGNIFICANCE: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/ß-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.
Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Vía de Señalización Wnt , Animales , Femenino , Humanos , Ratones , Proteína Axina/genética , Proteína Axina/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt3A/metabolismo , Proteína Wnt3A/genéticaRESUMEN
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.