Abstract 1121: ER-negative breast cancer survive mitochondrial IMS-stress via SIRT3 activation

Abstract

Abstract Mitochondrial dysfunction is central in carcinogenesis and has been associated with elevated levels of Reactive Oxygen Species (ROS). While moderate levels of ROS activate signaling cascade promoting tumor progression, high levels of ROS can lead to cell death. We previously demonstrated that Estrogen Receptor (ER)-positive breast cancer cells activate ER to overcome the mitochondrial impairment and reduce high levels of ROS induced by stress in the inter-mitochondrial membrane space (IMS). The ultimate outcome of ER activation is induction of a novel Unfolded Protein Response (UPR) that involves up-regulation of NRF-1, a major regulator of mitochondrial biogenesis as well as induction of OMI and proteasome, two critical elements of protein quality control required to monitor the quality of IMS proteins. In the present work, we have evidence that ER-negative breast cancer cells trigger a distinct mechanism to cope up with IMS-stress. Due to the lack of ER, the stress from the IMS is extended into the matrix of mitochondria leading to activation of the matrix deacetylase, SIRT3. SIRT3 is required to increase the antioxidant capacity by up-regulating the antioxidant enzyme, MnSOD and therefore reducing ROS. In addition, our results reveal that SIRT3 is essential for removal of the irreversible impaired mitochondria through mitophagy. Overall, our data indicate that ER-positive and ER-negative breast cancer induce different mechanism to conquer mitochondrial malfunction coupled with ROS overproduction and maintain their cellular integrity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1121. doi:1538-7445.AM2012-1121