title: CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with generally poor prognosis and no available targeted therapies, highlighting a critical unmet need to identify and characterize novel therapeutic targets. We previously demonstrated that CIB1 is necessary for cancer cell survival and proliferation via regulation of two oncogenic signaling pathways, RAF-MEK-ERK and PI3K-AKT. Because these pathways are often upregulated in TNBC, we hypothesized that CIB1 may play a broader role in TNBC cell survival and tumor growth. Methods utilized include inducible RNAi depletion of CIB1 in vitro and in vivo, immunoblotting, clonogenic assay, flow cytometry, RNA-sequencing, bioinformatics analysis, and Kaplan-Meier survival analysis. CIB1 depletion resulted in significant cell death in 8 of 11 TNBC cell lines tested. Analysis of components related to PI3K-AKT and RAF-MEK-ERK signaling revealed that elevated AKT activation status and low PTEN expression were key predictors of sensitivity to CIB1 depletion. Furthermore, CIB1 knockdown caused dramatic shrinkage of MDA-MB-468 xenograft tumors in vivo. RNA sequence analysis also showed that CIB1 depletion in TNBC cells activates gene programs associated with decreased proliferation and increased cell death. CIB1 expression levels per se did not predict TNBC susceptibility to CIB1 depletion, and CIB1 mRNA expression levels did not associate with TNBC patient survival. Our data are consistent with the emerging concept of non-oncogene addiction, where a large subset of TNBCs depend on CIB1 for cell survival and tumor growth, independent of CIB1 expression levels. Our data establish CIB1 as a novel therapeutic target for TNBC.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, 120 Mason Farm Rd Ste 3010, Chapel Hill, NC, 27599, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Black
authors.forename: J Chuck
authors.initials: JC
authors.lastname: Harrell
authors.forename: Tina M
authors.initials: TM
authors.lastname: Leisner
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fellmeth
authors.forename: Samuel D
authors.initials: SD
authors.lastname: George
authors.forename: Dominik
authors.initials: D
authors.lastname: Reinhold
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Baker
authors.forename: Corbin D
authors.initials: CD
authors.lastname: Jones
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Leslie V
authors.initials: LV
authors.lastname: Parise
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D051379:Mice; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054462:p21-Activated Kinases