title: High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1.
abstract: The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.
authors: Department of Clinical and Experimental Medicine, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. elin.karlsson@liu.se
authors: Elin
authors: E
authors: Karlsson
authors: Marie Ahnström
authors: MA
authors: Waltersson
authors: Josefine
authors: J
authors: Bostner
authors: Gizeh
authors: G
authors: Pérez-Tenorio
authors: Birgit
authors: B
authors: Olsson
authors: Anna-Lotta
authors: AL
authors: Hallbeck
authors: Olle
authors: O
authors: Stål
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000737:chemistry / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2