Abstract P1-07-06: Activation of oncogenic pathways by mitochondrial reprogramming in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TN BCa) Driver pathway is still poorly understood. Thus, it is important to identify the underlying mechanisms of triple negative breast cancer progression. Mitochondria, a semiautonomous organelle in cells, play an important role in cellular energy metabolism, free radical generation, and apoptosis. Mitochondria-nuclear crosstalk is a bidirectional pathway of communication between mitochondria and nucleus that influences many cellular and organismal activities. This crosstalk can regulate several oncogenic pathways involved in tumorigenesis. Using transmitochondrial cybrid (cybrid) technology, we generated different cybrid models under common nuclear background of TN BCa. Mitochondria from cells of different cancer potential including benign breast epithelium, moderately and highly metastatic breast cancer cell lines were used to understand cancer mitochondria regulated tumor pathways. Tumor and gene expression analysis suggested that among different cancer pathways, c-Src signaling pathway is one of the most consistently activated pathways in cybrids with TN BCa cancer mitochondria. Further analysis in parental cells and other tumor models suggested that autophosphorylation of c-Src is regulated by mitochondrial tumor characteristics. Our preliminary analysis also suggest that mitochondria targeted drugs are promising combination therapy for the management of Src-driven TN BCa. This finding is particularly important while considering the poor response rate observed after single drug therapy with Src family tyrosine kinase inhibitor Dasatinib in unselected TN BCa patients. Citation Format: Jun Hyoung Park, Santhosh Kumar, Sajna Vithayathil, Kavisha Arora, Nagireddy Putluri, Efrosini Tsouko, Taraka R Donti, Daniel E Frigo, Chad J Creighton, Michael T Lewis, Arun Sreekumar, Lee-Jun Wong, Benny Abraham Kaipparettu. Activation of oncogenic pathways by mitochondrial reprogramming in triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-06.