1. ¹Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
2. ²UKE Hamburg, Institute for Tumor Biology, Hamburg, Germany
3. ³Center for Bioinformatics, University of Hamburg, Hamburg, Germany
4. ⁴European Laboratory Association, Ibbenbueren/Osnabrück, Germany
5. ⁵Institute of Pathology, University of Muenster, Muenster, Germany
6. ⁶Institute of Gynecology and Obstetrics, University of Muenster, Muenster, Germany
7. ⁷Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
8. ⁸Department of Gynecology and Obstetrics, Breast Centre, Academic Hospital of University Bonn, Klinikum Lüdenscheid, Lüdenscheid, Germany
9. ⁹Celera Diagnostics, Alameda, CA, USA

Correspondence: Dr BH Brandt, UKE Hamburg, Institute for Tumor Biology, Martinistr. 52, 20246 Hamburg, Germany. E-mail: bu.brandt@uke.uni-hamburg.de

Received 3 April 2008; Revised 2 July 2008; Accepted 7 July 2008; Published online 12 August 2008.

Abstract

Gains of chromosomes 7p and 8q are associated with poor prognosis among oestrogen receptor-positive (ER+) stage I/II breast cancer. To identify transcriptional changes associated with this breast cancer subtype, we applied suppression subtractive hybridisation method to analyse differentially expressed genes among six breast tumours with and without chromosomal 7p and 8q gains. Identified mRNAs were validated by real-time RT–PCR in tissue samples obtained from 186 patients with stage I/II breast cancer. Advanced statistical methods were applied to identify associations of mRNA expression with distant metastasis-free survival (DMFS). mRNA expression of the key enzyme of cholesterol biosynthesis, squalene epoxidase (SQLE, chromosomal location 8q24.1), was associated with ER+ 7p+/8q+ breast cancer. Distant metastasis-free survival in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA in multivariate Cox analysis (P<0.001) in two independent patient cohorts of 160 patients each. The clinically favourable group associated with a low SQLE mRNA expression could be further divided by mRNA expression levels of the oestrogen-regulated zinc transporter LIV-1. The data strongly support that SQLE mRNA expression might indicate high-risk ER+ stage I/II breast cancers. Further studies on tumour tissue from standardised treated patients, for example with tamoxifen, may validate the role of SQLE as a novel diagnostic parameter for ER+ early stage breast cancers.