For Triple Negative BCa (TN BCa), there is a current lack of understanding of driver pathways and hence are often treated using more generic therapies. Currently there are no clinically accepted targets for the treatment for TN BCa and to predict its potential to metastasize. while BCa incidence is higher in Caucasian (CA) women, death due to BCa is higher in African American (AA) women. Importantly, AA patients are more likely to be diagnosed with triple negative (TN) BCa and at a more advanced stage than CA. Mitochondria is considered the energy house of the cell and has been strongly implicated in tumor development and progression and thus serving as a potential target for chemotherapy. With the advent of Transmitochondrial cybrid (cybrid) technology, it is now possible to examine the specific contribution of tumor-associated mitochondria to neoplastic growth and development under a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring mitochondria of interest with ?0 recipient cells (cells harboring ablated mitochondrial DNA). Using this technology in both an in vitro and in vivo setting, we have demonstrated a key role for mitochondrial retrograde regulation (MRR) progression of TN BCa. We have also identified critical regulation of post-translational modification of Src oncogenic pathway by cancer mitochondria. Our preliminary analysis using cybrids with mitochondria from AA and CA TN BCa cell lines suggest that mitochondrial retrograde regulation (MRR) of nuclear genes are different in AA and CA cells. Here we propose to combine Dr. Kaipparettu's (PI) expertise in BCa and cybrid technology with Dr. Lewis expertize in generating patient derived xenografts and Dr. Creighton's expertise in bioinformatics to evaluate a clinically challenging question, "How can we better distinguish AA and CA TN BCa by its MRR?" Strategically, we will use cybrid system generated from AA and CA TN BCa patients-derived xenografts to analyze the mitochondria specific alterations in metastatic BCa. ?0 cells from different TN breast-derived AA and CA nuclear background are already available in Kaipparettu lab. The cybrids thus generated will be confirmed for their mitochondrial function, nuclear origin by next-gen sequencing and evaluated for phenotypic changes using in vitro and in vivo tumor forming/invasion assays. Following this, cybrids with AA and CA mitochondria will be profiled for their Src pathway modification. To identify novel pathways, the MRR of cybrids will be analyzed by microarray and the gene expression will be examined using an established biostatistics and bioinformatics pipelines (Oncomine Concept Mapping) together with the biostatistician Dr. Creighton to generate oncogenic signatures and pathways associated with AA and CA TN BCa metastasis. The nominated pathways will be evaluated for their role in TN BCa progression using cell line and xenograft models. Overall, we expect to develop the first- of-its-kind mitochondria-driven oncogenic signature for AA and CA TN BCa progression. Clinically, we expect these to be translated to identify new drug targets for AA TN BCa.
Racial disparity exists in triple negative breast cancer, which is one of the aggressive subtypes of cancer, with higher number of incidence and mortality in young African American women. Though mitochondria play an important role in promoting cancer progression by retrograde regulation of nuclear genes and post-translation modification of oncoproteins, the role mitochondrial regulation in racial disparity of triple negative breast cancer has never been examined. Using a combination of cybrid technology together with oncogenic pathway analysis, this proposal aims to identify mitochondria-regulated cancer signatures for racial disparity in triple negative breast cancer.
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