Abstract 4327: Mitochondrial reprogramming in triple negative breast cancer progression

Unlike other subgroups of patients with breast cancer (BCa), for triple negative (TN) BCa, there is a current lack of understanding of driver pathways and hence are often managed using more generic therapies. Thus, it is important to identify the underlying mechanisms of triple negative breast cancer progression and its racial disparity. 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 that regulate cellular tumor characteristics. With the advent of transmitochondrial cybrid (cybrid) technology, it is now possible to examine the specific contribution of tumor-associated mitochondria in neoplastic growth and development under a defined common nuclear background. We used this model system to identify mitochondria regulated pathways in TN BCa. Among different oncogenic pathways, Src pathway is frequently over-expressed in TN BCa and Src inhibitors are proposed as one of their current treatments of choice. However, single drug therapy with Src inhibitors failed to control metastatic TN BCa in recent Phase-II trials. These highlight an important question on the mechanism behind the regulation of Src oncogenic signature in TN BCa. Using cybrid technology, we have discovered critical role of cancer mitochondria in the post-translational modification of Src oncogenic pathway. Interestingly we discovered that the Src autophosphorylation, which activate Src-mediated oncogenic pathway, depends on mitochondrial tumor characteristics. Specifically, our strong preliminary data suggest that mitochondrial reprogramming is a critical step in the autophosphorylation and activation of Src pathway in metastatic TN BCa cells. Our findings suggest mitochondria targeted drugs as promising combination therapy for the management of Src positive TN BCa. Citation Format: Junhyoung Park, Kavisha Arora, Sajna A. Vithayathil, Taraka R. Donti, Chad Creighton, Michael T. Lewis, Arun Sreekumar, Lee-Jun Wong, Benny A. Kaipparettu. Mitochondrial reprogramming in triple negative breast cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4327. doi:10.1158/1538-7445.AM2014-4327