title: KAT6A, a chromatin modifier from the 8p11-p12 amplicon is a candidate oncogene in luminal breast cancer.
abstract: The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Previous analyses in SUM-52 breast cancer cells showed amplification and overexpression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. KAT6A is a histone acetyltransferase previously identified as a fusion partner with CREB binding protein in acute myeloid leukemia. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal. Previous data from our laboratory identified FGFR2 as a driving oncogene in SUM-52 cells. The colony forming efficiency of SUM-52 KAT6A knockdown cells in the presence of FGFR inhibition was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a novel oncogene in breast cancers bearing the 8p11-p12 amplicon. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers.
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425. Electronic address: turnerbp@musc.edu.
authors.forename: Brittany
authors.initials: B
authors.lastname: Turner-Ivey
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
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.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Irish
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Christiana S
authors.initials: CS
authors.lastname: Kappler
authors.affiliation: Department of Public Health Science, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D011379:Prognosis; D011485:Protein Binding; D034622:RNA Interference; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D051548:Histone Acetyltransferases; C108712:KAT6A protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2