© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 2, 112-120,
January 19, 2000
© 2000 Oxford University Press
BCAR1, a Human Homologue of the Adapter Protein p130Cas, and Antiestrogen Resistance in Breast Cancer Cells
Affiliation of authors: Department of Pathology/Division of Molecular Biology, Josephine Nefkens Institute, University Hospital Rotterdam, The Netherlands.
Correspondence to: Arend Brinkman, Ph.D., Department of Pathology/Division of Molecular Biology, Josephine Nefkens Institute, University Hospital Rotterdam, Rm. Be 435a, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands (e-mail: brinkman{at}bidh.azr.nl).
BACKGROUND: Treatment of breast cancer with the antiestrogen tamoxifen is effective in approximately one half of the patients with estrogen receptor-positive disease, but tumors recur frequently because of the development of metastases that are resistant to tamoxifen. We have previously shown that mutagenesis of human estrogen-dependent ZR-75-1 breast cancer cells by insertion of a defective retrovirus genome caused the cells to become antiestrogen resistant. In this study, we isolated and characterized the crucial gene at the breast cancer antiestrogen resistance 1 (BCAR1) locus. METHODS/RESULTS: Transfer of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen-resistant phenotype on the recipient cells. The complete coding sequence of BCAR1 was isolated by use of exon-trapping and complementary DNA (cDNA) library screening. Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino acids that was strongly homologous to rat p130Cas-adapter protein. Genomic analysis revealed that BCAR1 consists of seven exons and is located at chromosome 16q23.1. BCAR1 transcripts were detected in multiple human tissues and were similar in size to transcripts produced by retrovirus-mutated ZR-75-1 cells. Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell proliferation in the presence of antiestrogens, confirming that BCAR1 was the responsible gene in the locus. CONCLUSIONS: Overexpression of the BCAR1 gene confers antiestrogen resistance on human ZR-75-1 breast cancer cells. Overexpression of BCAR1 in retrovirus-mutated cells appears to result from activation of the gene's promoter. The isolation and characterization of this gene open new avenues to elucidating mechanisms by which the growth of human breast cancer becomes independent of estrogen.
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