Mitochondrial haplotype alters mammary cancer tumorigenicity and metastasis in an oncogenic driver- dependent manner

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 and 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 v 293 v 225 days), fewer pulmonary metastases (5 v 7 v 15) and differences in size of lung metastases (1.2 v 1.4 v 1.0 mm diameter) compared to FVB/NJ mtDNA. Although PyMT-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.

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