Jiang S Y, Wolf D M, Yingling J M, Chang C, Jordan V C
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
Mol Cell Endocrinol. 1992 Dec;90(1):77-86. doi: 10.1016/0303-7207(92)90104-e.
The antiestrogen tamoxifen has been successfully used to control estrogen receptor (ER) and progesterone receptor positive breast cancer. However, the development of antiestrogen resistance is frequently observed in patients following long term treatment. We have studied the development of antiestrogen resistance in vitro and established an antiestrogen resistant variant of MCF-7 cells (clone 5C) after long term culture in estrogen free medium. The growth of clone 5C cells was not altered by either estradiol-17 beta or the antiestrogens 4-hydroxytamoxifen and ICI 164,384. Estrogen-stimulated progesterone receptor and reporter gene expression were markedly reduced in 5C cells compared to wild type MCF-7 cells. Only minor alteration in the levels of ER and no alteration in the affinity of ER for ligand were found in 5C cells. No mutation of ER cDNA in 5C cells was detected by polymerase chain reaction and DNA sequencing. This study demonstrates that change(s) in ER-mediated gene expression rather than the amino acid sequence of the ER itself may be associated with the development of at least one form of antiestrogen resistance.
抗雌激素药物他莫昔芬已成功用于控制雌激素受体（ER）和孕激素受体阳性的乳腺癌。然而，长期治疗的患者中经常观察到抗雌激素耐药性的出现。我们在体外研究了抗雌激素耐药性的发展，并在无雌激素培养基中长时间培养后建立了MCF-7细胞的抗雌激素耐药变体（克隆5C）。克隆5C细胞的生长不受17β-雌二醇或抗雌激素药物4-羟基他莫昔芬和ICI 164,384的影响。与野生型MCF-7细胞相比，雌激素刺激的孕激素受体和报告基因表达在5C细胞中明显降低。在5C细胞中，仅发现ER水平有轻微变化，而ER与配体的亲和力没有改变。通过聚合酶链反应和DNA测序未检测到5C细胞中ER cDNA的突变。这项研究表明，ER介导的基因表达变化而非ER本身的氨基酸序列变化可能与至少一种形式的抗雌激素耐药性的发展有关。
