Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway.
BACKGROUND
Tamoxifen is effective for endocrine treatment of oestrogen receptor-positive breast cancers but ultimately fails due to the development of resistance. A functional screen in human breast cancer cells identified two BCAR genes causing oestrogen-independent proliferation. The BCAR1 and BCAR3 genes both encode components of intracellular signal transduction, but their direct effect on breast cancer cell proliferation is not known. The aim of this study was to investigate the growth control mediated by these BCAR genes by gene expression profiling.


METHODS
We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF). A comparison with published gene expression data of cell models and breast tumours is made.


RESULTS
Relatively few changes in gene expression were detected in the BCAR-transfected cells, in comparison with the extensive and distinct differences in gene expression induced by oestrogen or EGF. Both BCAR1 and BCAR3 regulate discrete sets of genes in these ZR-75-1-derived cells, indicating that the proliferation signalling proceeds along distinct pathways. Oestrogen-regulated genes in our cell model showed general concordance with reported data of cell models and gene expression association with oestrogen receptor status of breast tumours.


CONCLUSIONS
The direct comparison of the expression profiles of BCAR transfectants and oestrogen or EGF-stimulated cells strongly suggests that anti-oestrogen-resistant cell proliferation is not caused by alternative activation of the oestrogen receptor or by the epidermal growth factor receptor signalling pathway.
Dorssers
Lambert C J
LC
Department of Pathology, Josephine Nefkens Institute, Rotterdam, The Netherlands. l.dorssers@erasmusmc.nl
van Agthoven
Ton
T
Brinkman
Arend
A
Veldscholte
Jos
J
Smid
Marcel
M
Dechering
Koen J
KJ
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D019313:BRCA1 Protein / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D011960:Receptors, Estrogen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; C118588:BCAR3 protein, human; D019313:BRCA1 Protein; D020662:Guanine Nucleotide Exchange Factors; D011960:Receptors, Estrogen; D013629:Tamoxifen; D066246:ErbB Receptors