Abstract A090: Mitochondrial genetics in the regulation of tumorigenicity and metastatic potential

• Published in: Molecular cancer research 2013-10, Vol.11 (10_Supplement), p.A090-A090
• Main Authors: Feeley, Kyle P., Bray, Alexander W., Fetterman, Jessica L., Westbrook, David G., Johnson, Larry W., Kesterson, Robert A., Welch, Danny R., Ballinger, Scott W.
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1557-3125.ADVBC-A090

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors combine to influence an individual's predilection for breast cancer and related metastatic tumor formation. The genetic component, in particular, has become the focus of emergent studies which have determined a role for nuclear genetic differences directing breast cancer susceptibility. Studies examining tumor latency and metastatic formation in mice have demonstrated clear differences between inbred strains. However, these studies fail to exclude the possibility that mitochondrial genetic inheritance is responsible for the observed changes in tumor onset and metastatic spread due to maternal inheritance of the mitochondrial genome. Although mitochondrial mutations within the tumor cell have recently been implicated as contributing to metastatic potential, studies have not directly addressed the effects of the mitochondrial DNA (mtDNA) background of the host on disease susceptibility. This work hypothesizes that the pre-existent “normal” mitochondrial haplotype harbored by an individual conveys risk in determining tumor latency and metastatic susceptibility. Furthermore, these changes in susceptibility will be accompanied by altered mitochondrial functional characteristics that can be attributed to differences in mitochondrial haplotype. Analysis of the direct contribution of mitochondrial DNA on tumorigenicity is made possible through the use of mitochondrial-nuclear exchange (MNX) mice in which nuclei from normal FVB mice (the background strain of the tg: MMTV-PyMT) were transferred onto cytoplasms containing C57BL/6 or BALB/c mitochondria. Crossing male FVB:tg:MMTV:PyMT mice with FVB(nDNA)C57BL/6(mtDNA) or FBV(nDNA)BALB/c(mtDNA) females maintained nuclear FVB nDNA and takes advantage of maternal inheritance of mtDNA. Present data indicate primary tumor latency segregating by mitochondrial DNA as PyMT-FVB wild-type animals develop primary tumors in 57 days compared to PyMT-FVB(n)C57BL/6(mt) which develop primary tumors in 65 days. Bioenergetic analyses using the Seahorse XF-24 as well as electron transport complex enzymatic assays will be conducted to more precisely delineate the functional metabolic differences contributing to altered tumorigenicity. MNX crosses suggest that cross-talk between mtDNA and nDNA has a greater influence on metastasis than previously appreciated and that mtDNA may be used clinically to improve patient prognosis. Citation Format: K