van den Berg H W, Lynch M, Martin J, Nelson J, Dickson G R, Crockard A D
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.
Br J Cancer. 1989 Apr;59(4):522-6. doi: 10.1038/bjc.1989.107.
A 6-month exposure of ZR-75-1 human breast cancer cells to tamoxifen (1 microM rising to 2 microM). resulted in a fall in oestrogen receptor (ER) levels from 225 fmol mg protein-1 to 56 fmol mg protein-1 while progesterone receptor (PGR) concentration fell from 63 fmol mg protein-1 to undetectable levels. Sensitivity to the anti-proliferative effects of tamoxifen was unchanged. A further 6 months' exposure to 4 microM tamoxifen resulted in loss of detectable ER and PGR and development of resistance to tamoxifen. Resistant cells, designated ZR-75-9a1, displayed morphological changes consistent with the acquisition of a less well differentiated phenotype. Flow cytometric studies demonstrated that the cell cycle distribution pattern of the resistant variant growing in the presence of 8 microM tamoxifen was identical to that of the untreated parent line, which showed marked accumulation of cells in G0/G1 when exposed to 8 microM tamoxifen. The resistant phenotype was not stable if cells were transferred to complete drug-free medium, but remained stable for at least 3 months in the presence of medium lacking oestrogenic activity. ZR-75-9a1 cells differ from previously reported tamoxifen-resistant variants of the MCF-7 line which retain ER and may prove a valuable model for the study of the development and stability of tamoxifen resistance in human breast cancer.
将ZR-75-1人乳腺癌细胞暴露于他莫昔芬（1微摩尔升至2微摩尔）6个月，导致雌激素受体（ER）水平从225飞摩尔/毫克蛋白降至56飞摩尔/毫克蛋白，而孕激素受体（PGR）浓度从63飞摩尔/毫克蛋白降至检测不到的水平。对他莫昔芬抗增殖作用的敏感性未变。再将细胞暴露于4微摩尔他莫昔芬6个月，导致可检测到的ER和PGR丧失，并产生对他莫昔芬的耐药性。命名为ZR-75-9a1的耐药细胞表现出形态学变化，与获得分化程度较低的表型一致。流式细胞术研究表明，在8微摩尔他莫昔芬存在下生长的耐药变体的细胞周期分布模式与未处理的亲代细胞系相同，亲代细胞系在暴露于8微摩尔他莫昔芬时，G0/G1期细胞明显积累。如果将细胞转移到完全无药物的培养基中，耐药表型不稳定，但在缺乏雌激素活性的培养基中至少可保持稳定3个月。ZR-75-9a1细胞不同于先前报道的MCF-7系他莫昔芬耐药变体，后者保留ER，可能是研究人乳腺癌中他莫昔芬耐药性的发生和稳定性的有价值模型。
