Cargando…

Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model

Successful cell replication requires both cell cycle completion and accurate chromosomal segregation. The tumor suppressor BRCA2 is positioned to influence both of these outcomes, and thereby influence genomic integrity, during meiotic and mitotic cell cycles. Accordingly, mutations in BRCA2 induce...

Descripción completa

Detalles Bibliográficos
Autores principales: Mensah, L., Ferguson, J. L., Shive, H. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413366/
https://www.ncbi.nlm.nih.gov/pubmed/30930946
http://dx.doi.org/10.1155/2019/9218251
_version_ 1783402803523223552
author Mensah, L.
Ferguson, J. L.
Shive, H. R.
author_facet Mensah, L.
Ferguson, J. L.
Shive, H. R.
author_sort Mensah, L.
collection PubMed
description Successful cell replication requires both cell cycle completion and accurate chromosomal segregation. The tumor suppressor BRCA2 is positioned to influence both of these outcomes, and thereby influence genomic integrity, during meiotic and mitotic cell cycles. Accordingly, mutations in BRCA2 induce chromosomal abnormalities and disrupt cell cycle progression in both germ cells and somatic cells. Despite these findings, aneuploidy is not more prevalent in BRCA2-associated versus non-BRCA2-associated human cancers. More puzzlingly, diploidy in BRCA2-associated cancers is a negative prognostic factor, unlike non-BRCA2-associated cancers and many other human cancers. We used a brca2-mutant/tp53-mutant cancer-prone zebrafish model to explore the impact of BRCA2 mutation on cell cycle progression, ploidy, and cancer-associated mortality by performing DNA content/cell cycle analysis on zebrafish germ cells, somatic cells, and cancer cells. First, we determined that combined brca2/tp53 mutations uniquely disrupt meiotic progression. Second, we determined that sex significantly influences ploidy outcome in zebrafish cancers. Third, we determined that brca2 mutation and female sex each significantly reduce survival time in cancer-bearing zebrafish. Finally, we provide evidence to support a link between BRCA2 mutation, tumor diploidy, and poor survival outcome. These outcomes underscore the utility of this model for studying BRCA2-associated genomic aberrations in normal and cancer cells.
format Online
Article
Text
id pubmed-6413366
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-64133662019-03-31 Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model Mensah, L. Ferguson, J. L. Shive, H. R. J Oncol Research Article Successful cell replication requires both cell cycle completion and accurate chromosomal segregation. The tumor suppressor BRCA2 is positioned to influence both of these outcomes, and thereby influence genomic integrity, during meiotic and mitotic cell cycles. Accordingly, mutations in BRCA2 induce chromosomal abnormalities and disrupt cell cycle progression in both germ cells and somatic cells. Despite these findings, aneuploidy is not more prevalent in BRCA2-associated versus non-BRCA2-associated human cancers. More puzzlingly, diploidy in BRCA2-associated cancers is a negative prognostic factor, unlike non-BRCA2-associated cancers and many other human cancers. We used a brca2-mutant/tp53-mutant cancer-prone zebrafish model to explore the impact of BRCA2 mutation on cell cycle progression, ploidy, and cancer-associated mortality by performing DNA content/cell cycle analysis on zebrafish germ cells, somatic cells, and cancer cells. First, we determined that combined brca2/tp53 mutations uniquely disrupt meiotic progression. Second, we determined that sex significantly influences ploidy outcome in zebrafish cancers. Third, we determined that brca2 mutation and female sex each significantly reduce survival time in cancer-bearing zebrafish. Finally, we provide evidence to support a link between BRCA2 mutation, tumor diploidy, and poor survival outcome. These outcomes underscore the utility of this model for studying BRCA2-associated genomic aberrations in normal and cancer cells. Hindawi 2019-02-26 /pmc/articles/PMC6413366/ /pubmed/30930946 http://dx.doi.org/10.1155/2019/9218251 Text en Copyright © 2019 L. Mensah et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Mensah, L.
Ferguson, J. L.
Shive, H. R.
Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title_full Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title_fullStr Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title_full_unstemmed Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title_short Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model
title_sort genotypic and phenotypic variables affect meiotic cell cycle progression, tumor ploidy, and cancer-associated mortality in a brca2-mutant zebrafish model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413366/
https://www.ncbi.nlm.nih.gov/pubmed/30930946
http://dx.doi.org/10.1155/2019/9218251
work_keys_str_mv AT mensahl genotypicandphenotypicvariablesaffectmeioticcellcycleprogressiontumorploidyandcancerassociatedmortalityinabrca2mutantzebrafishmodel
AT fergusonjl genotypicandphenotypicvariablesaffectmeioticcellcycleprogressiontumorploidyandcancerassociatedmortalityinabrca2mutantzebrafishmodel
AT shivehr genotypicandphenotypicvariablesaffectmeioticcellcycleprogressiontumorploidyandcancerassociatedmortalityinabrca2mutantzebrafishmodel