Sequence conservation of mitochondrial (mt)DNA during expansion of clonal mammary epithelial populations suggests a common mtDNA template in CzechII mice.

Autor: Johnson JR; Mammary Stem Cell Biology Section, National Cancer Institute, Bethesda, MD 20892, USA.; Department of Population Sciences, City of Hope, Duarte, CA 91107, USA., Lack JB; Bioinformatics Manager/Lead, NIAID Collaborative Bioinformatics Resource (NCBR) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Bethesda, MD 20894, USA., Boulanger CA; Mammary Stem Cell Biology Section, National Cancer Institute, Bethesda, MD 20892, USA., Ragle LE; Mammary Stem Cell Biology Section, National Cancer Institute, Bethesda, MD 20892, USA., Smith GH; Mammary Stem Cell Biology Section, National Cancer Institute, Bethesda, MD 20892, USA.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2020 Jan 14; Vol. 11 (2), pp. 161-174. Date of Electronic Publication: 2020 Jan 14 (Print Publication: 2020).
DOI: 10.18632/oncotarget.27429
Abstrakt: One major foundation of cancer etiology is the process of clonal expansion. The mechanisms underlying the complex process of a single cell leading to a clonal dominant tumor, are poorly understood. Our study aims to analyze mitochondrial DNA (mtDNA) for somatic single nucleotide polymorphisms (SNPs) variants, to determine if they are conserved throughout clonal expansion in mammary tissues and tumors. To test this hypothesis, we took advantage of a mouse mammary tumor virus (MMTV)-infected mouse model (CzechII). CzechII mouse mtDNA was extracted, from snap-frozen normal, hyperplastic, and tumor mammary epithelial outgrowth fragments. Next generation deep sequencing was used to determine if mtDNA " de novo " SNP variants are conserved during serial transplantation of both normal and neoplastic mammary clones. Our results support the conclusion that mtDNA " de novo " SNP variants are selected for and maintained during serial passaging of clonal phenotypically heterogeneous normal cellular populations; neoplastic cellular populations; metastatic clonal cellular populations and in individual tumor transplants, grown from the original metastatic tumor. In one case, a mammary tumor arising from a single cell, within a clonal hyperplastic outgrowth, contained only mtDNA copies, harboring a deleterious " de novo " SNP variant, suggesting that only one mtDNA template may act as a template for all mtDNA copies regardless of cell phenotype. This process has been attributed to "heteroplasmic-shifting". A process that is thought to result from selective pressure and may be responsible for pathogenic mutated mtDNA copies becoming homogeneous in clonal dominant oncogenic tissues.
Competing Interests: Conflicts of Interest The authors declare no potential conflicts of interest.
Databáze: MEDLINE