title: c-MYC is a radiosensitive locus in human breast cells.
abstract: Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Wade
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Sunter
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Fordham
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Long
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Masic
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Russell
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: V
authors.initials: V
authors.lastname: Rand
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C
authors.initials: C
authors.lastname: Elstob
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: N
authors.initials: N
authors.lastname: Bown
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Rowe
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C
authors.initials: C
authors.lastname: Lowe
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: G
authors.initials: G
authors.lastname: Cuthbert
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: S
authors.initials: S
authors.lastname: Bennett
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: S
authors.initials: S
authors.lastname: Crosier
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Bacon
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Onel
authors.affiliation: Department of Biology, University of York, Heslington, York, UK.
authors.forename: K
authors.initials: K
authors.lastname: Scott
authors.affiliation: Department of Histopathology, Harrogate and District NHS Foundation Trust, Harrogate District Hospital, Yorkshire, UK.
authors.forename: D
authors.initials: D
authors.lastname: Scott
authors.affiliation: Department of Radiation Oncology and Rubin Center for Cancer Survivorship, James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Travis
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: F E B
authors.initials: FE
authors.lastname: May
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Allan
mesh_terms: D001940:Breast / Q000166:cytology / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics; D002460:Cell Line; D056915:DNA Copy Number Variations; D005260:Female; D016259:Genes, myc; D006689:Hodgkin Disease / Q000532:radiotherapy; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics*