INCREASED RESISTANCE TO CYTOTOXIC AGENTS IN ZR75B HUMAN BREAST-CANCERCELLS TRANSFECTED WITH EPIDERMAL GROWTH-FACTOR RECEPTOR

Human breast cancer cells selected for multidrug resistance frequently overexpress ligands and receptors in the epidermal growth factor (EGF ) receptor family. To determine whether this overexpression contribute s to the drug resistant phenotype, EGF receptor transfected ZR75B huma n breast cancer cells were examined. Two EGF receptor overexpressing c lones were evaluated: clone 11 with >1 x 10(6) sites, and clone 13 wit h 310 000 receptor sites/cell. These were compared with clone 2-neo, w hich was transfected with the neomycin gene only and contained 43 000 receptor sites/cell. The EGF receptor overexpressing clones and the ne o transfected control clone displayed comparable growth rates. Cytotox icity analyses were performed with doxorubicin, vinblastine, cisplatin and 5-fluorouracil to determine the sensitivity of the clones to anti neoplastic drugs. The EGF receptor overexpressing clones were found to be 1.5-5.6 times more resistant to the four drugs tested. This increa se in the IC50 conferred a selective advantage when grown in the prese nce of 2, 3 and 6 ng/ml doxorubicin. Clone 13 cells overtook a mixed p opulation which began with clone 2-neo comprising 95% of the cells. Cl one 2-neo remained the dominant clone in the absence of drug. Finally, after long-term selection of the clones with 6 ng/ml doxorubicin, clo ne 2-neo became fourfold more resistant than the unselected clone 2-ne o, a level which was comparable to that found in the EGF receptor over expressing clones 11 and 13. No additional increase in resistance was observed for these clones, suggesting that clone 2-neo had developed a dditional resistance mechanisms. These results support the hypothesis that the EGF receptor pathway is able to confer a selective advantage to cells during drug exposure and potentially participates in the mult idrug resistant phenotype.