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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Development of anti-estrogen resistance limits the benefit of endocrine therapy of breast cancer. The mechanistic basis for resistance to the anti-estrogen tamoxifen may involve (epi)genetic alterations within tumor cells. We have initiated a random search for genes allowing estrogen-dependent ZR-75-1 human breast-cancer cells to proliferate in the presence of tamoxifen. The strategy was based on insertion mutagenesis of ZR-75-1 cells using defective retrovirus and subsequent identification of common integration sites. As an alternative approach to identify integration loci involved in anti-estrogen resistance, we have applied cell fusion. Integration regions from lethally irradiated, tamoxifen-resistant cells were transferred to hygromycin B-resistant ZR-75-1 cells. Somatic cell hybrids were established by selection for resistance to G418 (encoded by the integrated virus) and hygromycin B. Individual integration loci were thus separated among different cell hybrids and tested for their role in anti-estrogen resistance. Analysis of a panel of 29 somatic-cell hybrids revealed that tamoxifen resistance co-segregated with only 1 of the 2 integration loci present in the tamoxifen-resistant donor cell line. This locus was further identified as a common integration site in our panel of tamoxifen-resistant cell clones. Our results designate this integration site as the second breast-cancer-anti-estrogen-resistance locus (BCAR2), which most likely contains a gene responsible for the anti-estrogen-resistant phenotype in close proximity to the integrated virus. Our data also imply that individual genes can alter the estrogen dependency of human breast-cancer cells in a dominant manner in vitro.
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PMID:Identification of a novel breast-cancer-anti-estrogen-resistance (BCAR2) locus by cell-fusion-mediated gene transfer in human breast-cancer cells. 925 13

Endocrine treatment of breast cancer is widely applied and effective. However, in advanced disease cases, the tumors will eventually progress into an estrogen-independent and therapy-resistant phenotype. To elucidate the molecular mechanisms underlying this endocrine therapy failure, we applied retroviral insertion mutagenesis to identify the main genes conferring estrogen independence to human breast cancer cells. Estrogen-dependent ZR-75-1 cells were infected with replication-defective retroviruses followed by selection with the anti-estrogen 4-hydroxy-tamoxifen. In the resulting panel of 79 tamoxifen-resistant cell lines, the viral integrations were mapped within the human genome. Genes located in the immediate proximity of the retroviral integration sites were characterized for altered expression and their capacity to confer anti-estrogen resistance when transfected into breast cancer cells. Out of 15 candidate BCAR (breast cancer anti-estrogen resistance) genes, seven (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7, and TRERF1/BCAR2) were shown to directly underlie estrogen independence. Our results show that insertion mutagenesis is a powerful tool to identify BCAR loci, which may provide insights into the molecular and cellular mechanisms of breast tumor progression and therapy resistance thereby offering novel targets for the development of tailor-made therapeutical and prevention strategies.
Breast Cancer Res Treat 2009 Mar
PMID:Functional identification of genes causing estrogen independence of human breast cancer cells. 1835 53