Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

Abstract

Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis.

Oxidative phosphorylation inducers fight pathological angiogenesis

“…In RA, radiographic erosions were significantly associated with the JT haplogroup [62] and, in early RA, an association was reported between erosions and increased intraarticular blood flow [63]. The mtDNA haplogroup has also been related to cancer risk [64][65][66].…”

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…Crossing nDNA-matched mice with female MNX mice allows segregation of mtDNA influence from nuclear genes. Using this model, we demonstrated that the mitochondrial genome alters tumor progression and metastasis [62,63,59] in the PyMT model nearly identical to what was observed in the wild-type mouse crosses. Furthermore, crossing MNX mice with mice over-expressing the HER2/Neu oncogene, we observed driver-dependent alterations in tumorigenesis and metastasis [62].…”

“…Using this model, we demonstrated that the mitochondrial genome alters tumor progression and metastasis [62,63,59] in the PyMT model nearly identical to what was observed in the wild-type mouse crosses. Furthermore, crossing MNX mice with mice over-expressing the HER2/Neu oncogene, we observed driver-dependent alterations in tumorigenesis and metastasis [62]. While not the focus of this review per se , MNX mice have uncovered existence of mtDNA modifier loci in cardiovascular disease [61], atherosclerosis [61,64], and obesity [63], strongly supporting a closer look at mitochondrial quantitative trait loci [65,66].…”

“…It stands to reason that mitochondrial SNP/mutations may also differentially regulate tumorigenesis in the context of altered oncogenic drivers. Combinatorial effects of mtDNA QTL and nDNA QTL (including oncogenes) is supported by data showing that mtDNA SNP cooperate differentially with different oncogenic drivers to alter metastasis efficiency [62]. However, as identified below the context specific nature and association of specific mutations/polymorphisms requires much more in-depth analysis and experimentation.…”

Mitochondrial polymorphisms contribute to aging phenotypes in MNX mouse models

“…MNX mice contain nuclear DNA contribution from one strain of mice and mitochondrial DNA contribution from another strain. We previously showed that mitochondrial backgrounds selectively affect tumor latency [37,39], metastasis [37,39], obesity [38], and cardiovascular disease [15]. Additionally, mitochondrial genomic backgrounds also affect nuclear DNA methylation [38], histone marks (J. McGuire and D.R Welch, in preparation) and gene expression.…”