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Published on: May 18, 2020
Differential effects on tumor progression by APOBEC3A, APOBEC3B, and APOBEC3H Haplotype I in a breast cancer mouse
Milaid Granadillo Rodríguez1, Lai Wong1, Arzhang Shayeganmehr1
1Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Introduction:
The APOBEC3 family of cytidine deaminases induces somatic mutations that are highly prevalent in cancers, but the functional consequences remain largely unknown.
Methods:
To determine these consequences, we exposed MCF7 tumorigenic breast epithelial cells to APOBEC3A, APOBEC3B or APOBEC3H Haplotype I.
Results:
Comparative analysis between cells pre and post -APOBEC3 exposure revealed fewer deamination-dependent γH2AX foci post-APOBEC3 exposure, despite maintaining APOBEC3 protein expression. In a mouse xenograft model, high expressing, but not low expressing APOBEC3A-exposed cells caused increased tumor progression. In contrast, high expressing, but not low expressing APOBEC3B-exposed cells decreased tumor size. APOBEC3H Haplotype I-exposed cells stochastically increased tumor progression independent of expression levels. Consistent with tumor data, RNA-seq showed upregulation of tumor enhancing pathways only in cells that enhanced tumor progression.
Discussion:
The results indicate that in a breast cancer xenograft model, APOBEC3A and APOBEC3H Haplotype I are more likely to contribute to enhanced tumor progression than APOBEC3B.
Insights
The APOBEC3 family of cytidine deaminases impacts cancer progression. APOBEC3A and APOBEC3H increased tumor growth, while APOBEC3B reduced it in a breast cancer model.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3) family of cytidine deaminases is known to induce somatic mutations in cancer.
- However, the functional implications of these mutations and the specific roles of individual APOBEC3 members in cancer progression are not well understood.
Purpose of the Study:
- To investigate the functional consequences of APOBEC3A, APOBEC3B, and APOBEC3H Haplotype I exposure on breast cancer cells and tumor progression.
- To determine how different APOBEC3 members influence tumor growth and associated molecular pathways.
Main Methods:
- MCF7 tumorigenic breast epithelial cells were exposed to APOBEC3A, APOBEC3B, or APOBEC3H Haplotype I.
- Comparative analysis of DNA damage markers (γH2AX foci) was performed pre- and post-APOBEC3 exposure.
- A mouse xenograft model was used to assess tumor progression in response to APOBEC3 exposure.
- RNA sequencing (RNA-seq) was employed to analyze gene expression changes in exposed cells.
Main Results:
- APOBEC3 exposure led to fewer deamination-dependent γH2AX foci, despite sustained APOBEC3 protein expression.
- High expression of APOBEC3A correlated with increased tumor progression in the mouse xenograft model.
- High expression of APOBEC3B correlated with decreased tumor size.
- APOBEC3H Haplotype I exposure resulted in stochastic increases in tumor progression, irrespective of expression levels.
- RNA-seq data revealed upregulation of tumor-enhancing pathways specifically in cells that showed enhanced tumor progression.
Conclusions:
- APOBEC3A and APOBEC3H Haplotype I are more likely to promote tumor progression in a breast cancer xenograft model compared to APOBEC3B.
- The differential effects of APOBEC3 family members highlight their complex roles in cancer development and progression.
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