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K Unger, Department of Histopathology, Imperial College London, London, W12 0NN, United Kingdom
J Wienberg, Department Biologie II, Anthropologie und Humangenetik, Ludwig Maximilians Universität Muenchen, Martinsried, Germany
A Riches, Bute Medical School, University of St. Andrews, St Andrews, United Kingdom
L Hieber, Institut fuer Molekulare Strahlenbiologie, Helmholtz Zentrum Muenchen, Neuherberg, Germany
A Walch, Institut für Pathologie, Helmholtz Zentrum München, Neuherberg, Germany
A Brown, Institut fuer Molekulare Strahlenbiologie, Helmholtz Zentrum Muenchen, Neuherberg, Germany
P O’Brien, Cambridge University Centre for Veterinary Science, University of Cambridge, Cambridge, United Kingdom
C Briscoe, Bute Medical School, University of St. Andrews, St Andrews, United Kingdom
L Gray, Bute Medical School, University of St. Andrews, St Andrews, United Kingdom
E Rodriguez, Institut fuer Molekulare Strahlenbiologie, Helmholtz Zentrum Muenchen, Neuherberg, Germany
G Jackl, Institut fuer Strahlenbiologie, Helmholtz Zentrum Muenchen, Neuherberg, Germany
J Knijnenburg, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden University Medical Center, Leiden, Netherlands
G Tallini, Anatomia Patologica, Università di Bologna, Bologna, Italy
M Ferguson-Smith, Cambridge University Centre for Veterinary Science, University of Cambridge, Cambridge, United Kingdom
H Zitzelsberger, Institut fuer Molekulare Strahlenbiologie, Helmholtz Zentrum Muenchen, Neuherberg, Germany

Correspondence: Kristian Unger, Email: k.unger{at}imperial.ac.uk

Abstract

Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human cancer. Unlike copy number alterations, little is known about the role and occurrence of chromosomal rearrangements in breast cancer. This may be due to the fact that chromosome-based breakpoint analysis is widely restricted to cultured cells. In order to identify gene rearrangements in breast cancer we studied the chromosomal breakpoints in radiation-transformed epithelial breast cell lines using a high-resolution array-based approach using 1Mb BAC arrays. The breakpoints were further narrowed down by FISH with clones from the 32k BAC library. The analysis of the cell lines B42-11 and B42-16 revealed rearrangements of chromosomes 7, 8, 10 and 12. We identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 within the breakpoint regions. Quantitative RT-PCR showed a deregulated expression of all of these candidate genes except for Tbx5 and Tbx3. This is the first study demonstrating gene rearrangements and their deregulated mRNA expression in radiation-transformed breast cells. Since the gene rearrangements occurred in the transformed and tumourigenic cell lines only it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells and therefore might reflect early molecular events in breast carcinogenesis. Initial studies indicate that these gene alterations are also found in sporadic breast cancers.