GENETIC MECHANISMS OF ESTROGEN-INDEPENDENCE IN BREAST-CANCER

Endocrine therapy is effective in the treatment of breast cancer Adjuv ant treatment with tamoxifen reduces tumor recurrence and achieves inc reased survival. In metastatic disease, tamoxifen treatment accomplish es objective responses in +/- 50% of the patients with estrogen recept or-positive primary tumors. However, the response duration is limited due to the inevitable development of metastases resistant to tamoxifen . The mechanisms leading to tamoxifen resistance are largely unknown. We have set out to identify genetic pathways in the tumor cells causin g failure of tamoxifen therapy. We selected an estrogen-dependent huma n breast cancer cell line (ZR-75-1) and demonstrated that genetic and epigenetic alterations call change the hormone-response phenotype of t hese cells. Subsequently, we applied insertional mutagenesis with defe ctive retroviruses to these ZR-75-1 breast cancer cells. Integration o f a retrovirus in the cellular DNA alters the genome structure and may modify the expression of genes in its surroundings. As a result of th e altered gene expression, the biological phenotype of the infected ce ll may be changed. The infected ZR-75-1 cells were subjected to tamoxi fen selection and a panel of tamoxifen-resistant cell lines has been e stablished. Screening for a common integration site for the retrovirus has provided, so far, compelling evidence for the involvement of at l east one genetic locus (BCAR 1) in breast cancer antiestrogen resistan ce in vitro.