title: Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes.
abstract: Gene amplification is a common mechanism of oncogene activation in cancer. Several large-scale efforts aimed at identifying the comprehensive set of genomic regions that are recurrently amplified in cancer have been completed. In breast cancer, these studies have identified recurrently amplified regions containing known drivers such as HER2 and CCND1 as well as regions where the driver oncogene is unknown. In this study, we integrated RNAi-based functional genetic data with copy number and expression data to identify genes that are recurrently amplified, overexpressed and also necessary for the growth/survival of breast cancer cells. Further analysis using clinical data from The Cancer Genome Atlas specifically identified candidate genes that play a role in determining patient outcomes. Using this approach, we identified two genes, TCP1 and CCT2, as being recurrently altered in breast cancer, necessary for growth/survival of breast cancer cells in vitro, and determinants of overall survival in breast cancer patients. We also show that expression of TCP1 is regulated by driver oncogene activation of PI3K signaling in breast cancer. Interestingly, the TCP1 and CCT2 genes both encode for components of a multi-protein chaperone complex in the cell known as the TCP1 Containing Ring Complex (TRiC). Our results demonstrate a role for the TRiC subunits TCP1 and CCT2, and potentially the entire TRiC complex, in breast cancer and provide rationale for TRiC as a novel therapeutic target in breast cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: guests@musc.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Guest
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Kratche
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA; Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Aliccia
authors.initials: A
authors.lastname: Bollig-Fischer
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Ramsi
authors.initials: R
authors.lastname: Haddad
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D002470:Cell Survival; D056404:Chaperonin Containing TCP-1 / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C533298:CCT2 protein, human; C533304:TCP1 protein, human; D019869:Phosphatidylinositol 3-Kinases; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051057:Proto-Oncogene Proteins c-akt; D056404:Chaperonin Containing TCP-1
keywords: Breast cancer; CCT2; Driver oncogene; Gene amplification; TCP-1