Mitochondria-Nuclear Communication Regulates Epithelial-Mesenchymal Transition And Metastasis In Triple Negative Breast Cancer

Abstract For triple negative breast cancer (TNBC), the driver pathways are still poorly understood. Advances in cancer metabolism research over the last decade have enhanced and modified our understanding on Warburg effect. It is now known that mitochondria in tumors are not always defective in their ability to carry out oxidative phosphorylation. Instead, in proliferating cells, mitochondrial energy pathways are reprogrammed to meet the challenges of macromolecular synthesis and to escape from apoptosis. Tumor initiating cells (TICs) maintain cancer stem cell properties and are known to play significant role in TNBC metastasis. Mitochondrial retrograde regulation (MRR) is a bidirectional communication between mitochondria and nucleus. MRR is triggered by mitochondrial functional demands and it responds in a continuous manner to change metabolic needs of the cell. Using transmitochondrial cybrid (cybrid) technology, we generated different cybrid models under common nuclear backgrounds of benign breast epithelium or TNBC. Mitochondria from cells with different cancer potential such as benign breast epithelium, moderately metastatic and highly metastatic breast cancer cell lines were studied under the common nuclear background to understand MRR-regulated TIC properties and cancer pathways. Using genomic, metabolomic, and proteomic approaches, we confirmed the significance of mitochondrial character in the regulation of epithelial mesenchymal transition (EMT), TIC and metastatic properties. Altogether, our results suggest that MRR is critical in TNBC TIC character and stemness. Citation Format: Park JH, Jung KH, Sirupangi T, Vithayathil S, Jin F, Putluri V, Piyarathna DWB, Yotnda P, Bhat VB, Sreekumar A, Lewis MT, Coarfa C, Putluri N, Creighton CJ, Wong L-JC, Kaipparettu BA. Mitochondria-nuclear communication regulates epithelial-mesenchymal transition and metastasis in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-01-07.