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


METHODS
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.
Lundgren
Katja
K
Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Sweden.
Holm
Karolina
K
Nordenskjöld
Bo
B
Borg
Ake
A
Landberg
Göran
G
D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics*; D000071877:Checkpoint Kinase 1; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D051356:Cortactin / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D053200:Fas-Associated Death Domain Protein / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D017697:Premenopause; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D017384:Sequence Deletion; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics
D018931:Antineoplastic Agents, Hormonal; C530104:CCND1 protein, human; C495868:CTTN protein, human; D051356:Cortactin; D020847:Estrogen Receptor Modulators; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D009363:Neoplasm Proteins; D013629:Tamoxifen; D019938:Cyclin D1; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C515903:PAK1 protein, human; D054462:p21-Activated Kinases