Research article

Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer

Katja Lundgren¹ , Karolina Holm² , Bo Nordenskjöld^3,4 , Åke Borg² and Göran Landberg¹

¹  Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, SE-205 02, Sweden

²  Department of Clinical Sciences, Division of Oncology, Lund University, Lund, SE-221 85, Sweden

³  Department of Oncology, Borås Hospital, Borås, SE-501 82, Sweden

⁴  Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden

author email corresponding author email

Breast Cancer Research 2008, 10:R81doi:10.1186/bcr2150

Published:	29 September 2008

Abstract

Introduction

The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, namely CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Over-expression of cyclin D₁ protein, however, confers tamoxifen resistance but not a tamoxifen-induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein over-expression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we examined a selected marker for this event.

Method

Array comparative genomic hybridization analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients who were randomly assigned to either tamoxifen or no adjuvant treatment. The protein expression was also compared with gene expression data in a subset of 56 breast cancer samples.

Results

Cortactin and FADD (Fas-associated death domain) over-expression was linked to CCND1 amplification, determined by fluorescence in situ hybridization, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1 (checkpoint kinase 1), was associated with an impaired tamoxifen response, and interestingly with low proliferative breast cancer of low grade. For Pak1 (p21-activated kinase 1) and cyclin D₁ the protein expression corresponded to the gene expression data.

Conclusions

The results indicate that many 11q13 associated gene products are over-expressed in conjunction with cyclin D₁ but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response.