Abstract A05: Coordinated control of protein synthesis by mTORC1 and RSKs in triple-negative breast cancer (TNBC)

Abstract

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors that do not express ER, PR or HER2 receptors. These tumors respond to conventional chemotherapy but have a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis compared with other breast cancer subtypes. Unfortunately, unlike ER+ and HER2+ subtypes, targeted therapies have not been validated to treat TNBC yet. For these reasons, our goal is to identify molecular drivers of TNBC that could be therapeutically targeted to improve patient outcome. Two major signaling pathways PI3K/AKT/mTOR and Raf/MEK/ERK are frequently up-regulated in TNBC. Targeting these pathways with specific inhibitors reduces proliferation of TNBC cell lines in preclinical studies, although combined treatment is required to prevent the activation of compensatory mechanisms between pathways and, therefore, the development of resistance. Interestingly, the ERK substrates p90 Ribosomal S6 Kinases (RSKs) regulate mTORC1 activity and/or mTORC1 downstream targets implicated in the control of translation initiation complex eIF4F and, in turn, protein synthesis. Therefore, these proteins integrate PI3K/AKT/mTOR and Raf/MEK/ERK pathways to regulate protein synthesis. Based on these data, we have investigated the contribution of mTORC1 and RSKs to the control of eIF4F activity and protein synthesis in MDA-MB-231 cells, TNBC cells with constitutively up-regulated ERK pathway. Here we show that mTORC1 and RSKs activate the translation initiation factor eIF4B and promote the degradation of the tumor suppressor PDCD4, which results in increased helicase activity of eIF4A, a component of eIF4F initiation complex, in MDA-MB-231 cells. However, regulation of eIF4A activity through eIF4B and PDCD4 relies on mTORC1 in ER-positive MCF7 cells with constitutively up-regulated PI3K/AKT/mTOR pathway. Additionally, we observe RSK-dependent increase in the translation of mRNAs with highly structured 5′UTR that encode factors involved in cell proliferation and survival in MDA-MB-231 cells. The contribution of mTORC1 and individual RSK isoforms (RSK1-4) to these processes is being evaluated upon specific stimulation of each pathway in TNBC cells. We are also investigating the role of the translational control by mTORC1 and RSKs in cellular proliferation, survival, migration and invasion. In summary, our results indicate that both mTORC1 and RSKs translationally regulate the expression of key factors involved in cell transformation and tumorigenesis in TNBC MDA-MB-231 cells, while these regulatory mechanisms rely on mTORC1 in ER-positive MCF7 cells. Citation Format: Rafael Cuesta, Marina K. Holz. Coordinated control of protein synthesis by mTORC1 and RSKs in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A05.