PROJECT SUMMARY
Highly recurrent and metastatic triple-negative breast cancer (TNBC) is predominant among young African
American (AA) compared to European American (EA) women. Although mitochondrial DNA alterations play an
essential role in tumor recurrence and metastasis, the mitochondrial genetic basis of TNBC racial disparity
remains largely unknown. Mitochondria are unique organelles within the cells (having their own DNA) and are
an integral part of the oxidative phosphorylation system (OXPHOS) for generating cellular ATP. They are
composed of five complexes (I-V), which are assembled from multiple polypeptides- some encoded by mtDNA
and others by nuclear DNA (nDNA). The human mtDNA is a 16.5-kb double-stranded closed circular molecule,
which codes for the 12S and 16S rRNAs, 22 tRNAs, and 13 proteins essential for the mt respiratory complex
(RC). Most human cells contain hundreds of copies of mtDNA and nearly all these mtDNA copies are identical,
i.e., homoplasmic at birth as the mtDNA follows a strict maternal mode of inheritance. The mutation rate in
mtDNA is approximately 10 times higher than that of the nuclear DNA and much easier to detect in cancer cells
because of the high copy number. Studies from our lab and others have identified somatic mtDNA mutations in
various cancers and demonstrated their role in cancer progression, implicating a role of mtDNA mutation in
human tumorigenesis. Extracellular vesicles (EVs) harboring nucleic acids, proteins, and lipids are important
determinants of tumorigenesis and promising for biomarker development. However, a comprehensive analysis
of mtDNA alterations in triple-negative breast cancer racial disparity and their potential in noninvasive biomarker
development remains largely unknown. In Aim 1, we will examine the pattern of the pre-optimized panel of 11-
mtDNA mutations in EA and AA-TNBCs. This approach will enable us to validate the aggressive tumor-
signature mtDNA mutational events and to better predict metastatic recurrence early and guide treatment
planning. In Aim 2, we will measure the above panel of mtDNA mutations in the circulating EVs of all the EA
and AA patients of Aim 1. Highly sensitive and accurate detection of the tumor-signature mtDNA mutations
in the circulation as a function of progression will allow us to detect invasive lesions early and better predict
metastatic recurrence and monitor therapeutic response. In the longer run, this research will lead to the
development of routine clinical assays to detect disparate tumor-signature hotspot mtDNA mutations and
measure mtDNA contents in extracellular vesicles for early diagnosis, recurrence prediction and treatment
planning of the racially disparate population.
