Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential

Abstract

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual’s predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial-nuclear exchange (MNX) mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects.

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

“…Recently, we determined that the mitochondrial genome influenced the process of metastasis in addition to nuclear genetic contributors (27). To determine whether mitochondrial genetics could be playing a role in metastasis, mitochondrial-nuclear exchange (MNX) mice were generated that have the same nuclear background with different mitochondrial backgrounds (28, 29).…”

“…To determine whether mitochondrial genetics could be playing a role in metastasis, mitochondrial-nuclear exchange (MNX) mice were generated that have the same nuclear background with different mitochondrial backgrounds (28, 29). These mice were made by enucleating a fertilized oocyte of one strain of mouse, leaving the cytoplasm and mitochondria, and then transferring a karyoplast from another mouse strain (27–29). These mouse strains are designated as nuclear background-mt MNX (mtDNA Background) (e.g., the MNX strain FVB/NJ-mt MNX(C57BL/6J) has the FVB/NJ nucleus and C57BL/6J mitochondrial DNA).…”

Understanding Mitochondrial Polymorphisms in Cancer

“…The authors discovered that FVB n mice with mtDNA from the C57BL/6J (BL/6 mt ) strain had an increased primary PyMT tumor latency ($65 days) when compared with FVB n mice with mtDNA from the FVB/NJ (FVB mt ) or BALB/cJ (BALB/c mt ) strain ($59 and $52 days, respectively). Furthermore, FVB n mice with mtDNA from the BALB/cJ (BALB/c mt ) strain developed larger individual lung metastases (in cm 2 ), indicating an increased metastatic burden when compared with FVB n mice containing mtDNA from the C57BL/6J (BL/6 mt ) strain (35). Thus, these results suggest that the mitochondrial genome of an individual may influence disease progression.…”

“…Previously, Ballinger and Welch had utilized MNX mice to study how mtDNA impacts cancer progression (35). Strains examined include C57BL/6J, FVB/NJ, and BALB/cJ.…”

“…Strains examined include C57BL/6J, FVB/NJ, and BALB/cJ. To investigate the role of mtDNA in breast cancer, female MNX mice were crossed with males carrying a PyMT transgene to produce mice hemizygous for PyMT with mtDNA from different genetic backgrounds (35). The authors discovered that FVB n mice with mtDNA from the C57BL/6J (BL/6 mt ) strain had an increased primary PyMT tumor latency ($65 days) when compared with FVB n mice with mtDNA from the FVB/NJ (FVB mt ) or BALB/cJ (BALB/c mt ) strain ($59 and $52 days, respectively).…”