Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment.
The pure steroidal anti-estrogens ICI 164,384 and ICI 182,780 are very potent growth inhibitors of the estrogen receptor-positive human breast cancer cell line MCF-7. However, long-term treatment of MCF-7 cells with 10(-7) M concentrations of these compounds results in selection of proliferating colonies of resistant cells. Our report describes 4 ICI 164,384- and 3 ICI 182,780-resistant MCF-7 sublines established after long-term treatment. Resistant sublines are estrogen receptor-positive, and all sublines have lost expression and estrogen inducibility of the progesterone receptor protein. Based on IC50 concentrations, all tested resistant sublines had a reduced sensitivity to pure anti-estrogens on the order of 100- to 1000-fold compared with parent MCF-7 cells. All resistant cell lines have survived propagation for more than 15 subcultivations in the presence of 10(-7) M pure anti-estrogen. The MCF-7/182R-6 subline has been tested for stability of resistance and appeared to be stably resistant after 13 weeks of propagation without the selective pressure of ICI 182,780. Cell lines resistant to the ICI 182,780 compound are cross-resistant to the ICI 164,384 compound and vice versa. However, the sublines resistant to pure antiestrogens are sensitive to tamoxifen. Our results show that although the pure steroidal anti-estrogens are very potent growth inhibitors, they do not circumvent development of resistance.
Lykkesfeldt
A E
AE
Department of Tumor Endocrinology, Danish Cancer Society, Copenhagen.
Larsen
S S
SS
Briand
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000648:ultrastructure; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C051781:ICI 164384