BRCA Status Dictates Wnt Responsiveness in Epithelial Ovarian Cancer
Recommended Citation
Chehade H, Gogoi R, Adzibolosu NK, Galoforo S, Fehmi RA, Kheil M, Fox A, Kim S, Rattan R, Hou Z, Morris RT, Matherly LH, Mor G, and Alvero AB. BRCA status dictates Wnt responsiveness in epithelial ovarian cancer. Cancer Res Commun 2024.
Document Type
Article
Publication Date
8-1-2024
Publication Title
Cancer Res Commun
Abstract
UNLABELLED: 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/β-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/β-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/β-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 β-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3β. 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/β-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.
Medical Subject Headings
Animals; Female; Humans; Mice; Axin Protein; beta Catenin; BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Mutation; Ovarian Neoplasms; Wnt Signaling Pathway; Wnt3A Protein
PubMed ID
39028933
ePublication
ePub ahead of print
Volume
4
Issue
8
First Page
2075
Last Page
2088
