title: MYC is amplified in BRCA1-associated breast cancers.
abstract: OBJECTIVE
  Germ-line mutations in the BRCA1 tumor suppressor gene predispose to early onset breast cancers with a distinct phenotype characterized by high tumor grade, aneuploidy, high proliferation rate, and estrogen receptor-negativity. The molecular mechanisms and cooperative oncogenes contributing to multistep tumor progression in cells lacking BRCA1 are not well defined. To examine whether C-MYC (MYC), a transforming oncogene associated with genetic instability, contributes to multistep tumor progression in BRCA1-associated breast cancer, we have analyzed tumors from women with hereditary BRCA1-mutated and sporadic breast cancers.
  
  
  METHODS
  We performed fluorescence in situ hybridization using a MYC:CEP8 assay on formalin-fixed paraffin-embedded tumor tissues from 40 women with known deleterious germ-line BRCA1 mutations and 62 sporadic cases, including 20 cases with hypermethylation of the BRCA1 gene promoter.
  
  
  RESULTS
  We observed a MYC:CEP8 amplification ratio >/=2 in 21 of 40 (53%) BRCA1-mutated tumors compared with 14 of 62 (23%) sporadic tumors (P = 0.003). Of the 14 sporadic cases with MYC amplification, 8 (57%) were BRCA1-methylated. In total, MYC amplification was found in a significantly higher proportion of tumors with BRCA1 dysfunction (29 of 60, 48% versus 6 of 42, 14%; P = 0.0003). In a multivariable regression model controlling for age, tumor size, and estrogen receptor status, BRCA1-mutated tumors demonstrated significantly greater mean MYC:CEP8 ratio than sporadic tumors (P = 0.02).
  
  
  CONCLUSIONS
  Our data indicate that MYC oncogene amplification contributes to tumor progression in BRCA1-associated breast cancers. Thus, we conclude that the aggressive histopathological features of BRCA1-associated tumors are in part due to dysregulated MYC activity.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, Illinois 60637-1463, USA.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Grushko
authors.forename: James J
authors.initials: JJ
authors.lastname: Dignam
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Anne M
authors.initials: AM
authors.lastname: Blackwood
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Karin K
authors.initials: KK
authors.lastname: Ridderstråle
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Anderson
authors.forename: Min-Jie
authors.initials: MJ
authors.lastname: Wei
authors.forename: April J
authors.initials: AJ
authors.lastname: Adams
authors.forename: Fitsum G
authors.initials: FG
authors.lastname: Hagos
authors.forename: Lise
authors.initials: L
authors.lastname: Sveen
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
mesh_terms: D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D002455:Cell Division; D019175:DNA Methylation; D018450:Disease Progression; D019398:Genes, BRCA1; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc