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Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence (TIS) and discovered that Bcl2-associated athanogene 3 (Bag3) is upregulated after adriamycin treatment in MCF7 cells. Bag3 protein is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major signaling pathways. Mass Spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin in favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in TIS by activation of extracellular signal-regulated kinase1/2 (ERK1/2). Bag3 and MVP were required for ERK1/2 activation in response to adriamycin and silencing either gene product decreased cell survival in response to the drug. An increase in nuclear accumulation of MVP is observed during TIS and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We demonstrate that Bag3 and MVP are expressed in a panel of diverse breast cancer cell lines and human tumor samples from patients. Silencing of Bag3 and MVP shifts the response to apoptosis and regulates ERK1/2 signaling in ER positive MCF7, ZR751 cell lines and triple negative MDA-MB-231 and MDA-MB-468 cells. Overall this study highlights Bag3-MVP as an important complex that regulates a potent pro-survival signaling pathway in breast cancer. Citation Format: Martina Pasillas, Sarah Shields, Rebecca Reilly, Laoighse Mulrane, Jan Strnadnel, Karin Jirstrom, Darran O Connor, William Gallagher, Steven Gonias, Judith Coppinger. Bcl2-associated athanogene 3 and major vault protein regulate cell survival and resistance to apoptosis in senescent cells by regulating ERK activation. [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 LB-18. doi:10.1158/1538-7445.AM2014-LB-18