All ETDs from UAB

Advisory Committee Chair

Scott W Ballinger

Advisory Committee Members

Danny R Welch

Aimee Landar

Douglas R Hurst

Richard D Lopez

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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 were 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-FVBn:C57mt which develop primary tumors in 65 days and PyMT-FVBn:BALBcmt animals having detectable tumors in 53 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. MNX crosses additionally 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.

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