Abstract 3055: Regulation of mitochondria-nuclear crosstalk in triple negative breast cancer

Driver pathways of triple negative breast cancer (TN BCa) is still poorly understood. Thus, it is important to identify the underlying mechanisms of TN BCa progression. Importantly, African American and Hispanic patients are more likely to be diagnosed of BCa at a younger age, have a higher probability of developing TN BCa. They also diagnosed with a more advanced stage of the disease compared to Caucasian women. Src oncognenic pathway is one of the major tumor driving mechanisms in TN BCa. Src pathway is frequently over-expressed in TN BCa and Src inhibitors are one of their current treatments of choices. However, recent single drug therapy Phase-II trials with Src inhibitors failed to control unselected metastatic TN BCa. This raises some important questions on the underlying mechanism in the regulation of Src in TN BCa especially in aggressive metastatic BCa. 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. Extensive analysis of cybrid models as well as confirmation in parental cell lines and other tumor models suggested that autophosphorylation of c-Src is regulated by mitochondrial tumor characteristics. Ongoing studies using knock-down and over expression approaches focus on the role of specific mitochondrial proteins that are responsible for mitochondria-nuclear crosstalk and the regulation oncopathways in TN BCa. Citation Format: Jun H. Park, Sajna A. Vithayathil, Nagireddy Putluri, Efrosini Tsouko, Taraka R. Donti, Daniel E. Frigo, Chad J. Creighton, Michael T. Lewis, Arun Sreekumar, Lee-Jun Wong, Benny A. Kaipparettu. Regulation of mitochondria-nuclear crosstalk in triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3055. doi:10.1158/1538-7445.AM2015-3055