title: A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation.
abstract: RNA interference has boosted the field of functional genomics, by making it possible to carry out 'loss-of-function' screens in cultured cells. Here, we performed a small interfering RNA screening, in three breast cancer cell lines, for 101 candidate driver genes overexpressed in amplified breast tumors and belonging to eight amplicons on chromosomes 8q and 17q, investigating their role in cell survival/proliferation. This screening identified eight driver genes that were amplified, overexpressed and critical for breast tumor cell proliferation or survival. They included the well-described oncogenic driver genes for the 17q12 amplicon, ERBB2 and GRB7. Four of six other candidate driver genes-RAD21 and EIF3H, both on chromosome 8q23, CHRAC1 on chromosome 8q24.3 and TANC2 on chromosome 17q23-were confirmed to be driver genes regulating the proliferation/survival of clonogenic breast cancer cells presenting an amplification of the corresponding region. Indeed, knockdown of the expression of these genes decreased cell viability, through both cell cycle arrest and apoptosis induction, and inhibited the formation of colonies in anchorage-independent conditions, in soft agar. Strategies for inhibiting the expression of these genes or the function of the proteins they encode are therefore of potential value for the treatment of breast cancers presenting amplifications of the corresponding genomic region.
authors.affiliation: CNRS, UMR 144.
authors.forename: Sardar Faisal
authors.initials: SF
authors.lastname: Mahmood
authors.forename: Nadège
authors.initials: N
authors.lastname: Gruel
authors.forename: Elodie
authors.initials: E
authors.lastname: Chapeaublanc
authors.forename: Aurianne
authors.initials: A
authors.lastname: Lescure
authors.forename: Thouis
authors.initials: T
authors.lastname: Jones
authors.forename: Fabien
authors.initials: F
authors.lastname: Reyal
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.forename: Virginie
authors.initials: V
authors.lastname: Raynal
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Franck
authors.initials: F
authors.lastname: Perez
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.forename: Elaine
authors.initials: E
authors.lastname: Del Nery
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard-Pierrot
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D002898:Chromosomes, Human, Pair 8; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D009698:Nucleoproteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C413904:CHRAC1 protein, human; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009698:Nucleoproteins; D010750:Phosphoproteins; D011506:Proteins; C429022:RAD21 protein, human; D034741:RNA, Small Interfering; C588271:TANC2 protein, human