Abstract 4326: Mitochondrial genetics and cellular metabolism regulate tumorigenicity and metastatic potential

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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 many emergent studies. A renewed focus on cancer metabolism and the Warburg Effect has similarly cast a spotlight on the role, if any, of the mitochondrion in directing disease progression. 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 FVB(nDNA)BALB/c(mtDNA) females maintained nuclear FVB nDNA and takes advantage of maternal inheritance of mtDNA. These PyMT transgene positive female progeny are then scored for primary tumor onset and pulmonary metastatic density. 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 and PyMT-FVB(n)BALB/c(mt) animals having detectable tumors in 52 days. One group of animals were aged 40 days following primary tumor detection and a second group were sacrificed when aged to 70 days, allowing for evaluation of metastatic severity and confirmation of differential primary tumor growth, respectively. 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. To address those mitochondrial differences, primary mammary epithelial cells were isolated from resected tumors which were then assessed for Complex I and Complex IV activity. In addition, isolated mammary epithelial cells from tumor and healthy animals had bioenergetic profiles generated using the Seahorse XF24 analyzer. Markers of ROS production will also be assessed as they too have been implicated increasingly frequently in cancer aggressiveness. Citation Format: Kyle P. Feeley, Alexander W. Bray, Jessica L. Fetterman, David G. Westbrook, Larry W. Johnson, Robert A. Kesterson, Danny R. Welch, Scott W. Ballinger. Mitochondrial genetics and cellular metabolism regulate tumorigenicity and metastatic potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4326. doi:10.1158/1538-7445.AM2014-4326