Our research focuses on identifying and characterizing genetic and molecular mediators of BRCA2– and TP53-associated carcinogenesis, and uses the zebrafish model as a unique and powerful in vivo system for these investigations. Most Brca2-mutant mouse models exhibit early embryonic lethality in the homozygous condition, limiting the types of studies that can be achieved with these models. We developed and characterized the first brca2-mutant zebrafish model. Zebrafish with homozygous brca2 mutation are fully viable and survive to adulthood, providing a key advantage over Brca2-mutant mouse models.
We have used the zebrafish model to provide novel insight into the effects of BRCA2 mutation on development, gonadogenesis, and tumorigenesis. We have also identified conserved mechanisms of BRCA2-associated carcinogenesis in zebrafish, such as the collaborative effects of brca2 and tp53 on cancer susceptibility; loss of heterozygosity in zebrafish cancers as a contributor to carcinogenesis; and impact of genotype and sex on tumor ploidy and survival outcome. These studies support use of the zebrafish model for investigating genetic and molecular events that drive BRCA2-associated cancer development.
Our current focus is to identify key events occurring in cancer onset that are linked to heritable BRCA2 and TP53 mutations. Using both cell-based systems and zebrafish models, we seek to understand mechanisms that enhance or suppress the potential for mutant cells to undergo transformation and initiate cancer development.
Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model. J Oncol. 2019;2019:9218251. doi: 10.1155/2019/9218251. eCollection 2019. PubMed PMID: 30930946; PubMed Central PMCID: PMC6413366.
Histologic and Immunohistochemical Analyses of Soft Tissue Sarcomas From brca2-Mutant/ tp53-Mutant Zebrafish Are Consistent With Neural Crest (Schwann Cell) Origin. Vet Pathol. 2017 Mar;54(2):320-327. doi: 10.1177/0300985816669406. Epub 2016 Nov 24. PubMed PMID: 27879444.
BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. PLoS One. 2014;9(1):e87177. doi: 10.1371/journal.pone.0087177. eCollection 2014. PubMed PMID: 24489863; PubMed Central PMCID: PMC3906131.
brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis. Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19350-5. doi: 10.1073/pnas.1011630107. Epub 2010 Oct 25. PubMed PMID: 20974951; PubMed Central PMCID: PMC2984219.