title: Functional identification of genes causing estrogen independence of human breast cancer cells.
abstract: 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.
authors: Department of Pathology, Josephine Nefkens Institute, Be 432, Erasmus MC-University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, CA, 3000, The Netherlands.
authors: Ton
authors: T
authors: van Agthoven
authors: Jos
authors: J
authors: Veldscholte
authors: Marcel
authors: M
authors: Smid
authors: Thecla L A
authors: TL
authors: van Agthoven
authors: Lilian
authors: L
authors: Vreede
authors: Marieke
authors: M
authors: Broertjes
authors: Ingrid
authors: I
authors: de Vries
authors: Danielle
authors: D
authors: de Jong
authors: Roya
authors: R
authors: Sarwari
authors: Lambert C J
authors: LC
authors: Dorssers
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D016254:Mutagenesis, Insertional; D012190:Retroviridae; D016662:Virus Integration
chemical_list: D004967:Estrogens