Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice.
Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice.
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发表时间：
2000-11
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通讯作者：
J. M. Schafer;E. Lee;E. Lee;Ruth M. O’Regan;K. Yao;V. Jordan
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作者：
J. M. Schafer;E. Lee;E. Lee;Ruth M. O’Regan;K. Yao;V. Jordan
MCF-7细胞常规用于研究他莫昔芬刺激的体内耐药性。然而，与MCF-7细胞不同，T47 D细胞表达突变型p53蛋白，并在体外长期雌激素剥夺期间失去雌激素受体（ER）[Pink et al.，Br. J. Cancer，74：1227-1236，1996（erratum，Br. J. Cancer，75：1557，1997）]。因此，T47 D肿瘤对长期他莫昔芬治疗的反应可能与MCF-7肿瘤不同。卵巢切除的无胸腺小鼠双侧乳房脂肪垫注射T47 D细胞（5 × 10（5））。建立了一个快速生长的雌二醇反应性肿瘤（T47 D：E2），每天给予0.5 mg他莫昔芬阻断雌激素刺激的生长。在随后的实验中，低剂量的他莫昔芬（0.17 mg或0.5 mg）在14周时没有产生他莫昔芬刺激的肿瘤，而高剂量的他莫昔芬（1.5 mg）在8周时持续产生他莫昔芬刺激的肿瘤（T47 D：Tam; 17个肿瘤/20个部位）。相比之下，1.5 mg他莫昔芬产生他莫昔芬刺激的MCF-7肿瘤（MCF-7：Tam 2）的速度较慢（20周），且不太一致（14个肿瘤/26个部位）。当T47 D：Tam肿瘤传代时，使用1.5 mg他莫昔芬或1 cm雌二醇胶囊（绝经前水平）时生长最大，MCF-7：Tam 2肿瘤获得了类似的结果。有趣的是，当用0.5 mg他莫昔芬治疗T47 D：Tam肿瘤时，肿瘤仅生长至最大50%。所有来源于MCF-7和T47 D细胞的肿瘤都以相似的水平表达ER;因此，他莫昔芬没有选择ER阴性肿瘤。总之，我们已经表明，他莫昔芬刺激的T47 D p53突变型肿瘤可以快速发展与高剂量治疗（1.5毫克，每天）。该模型的结果为研究突变型p53乳腺肿瘤患者对佐剂他莫昔芬的耐药性的快速发展提供了新的机会。
MCF-7 cells are used routinely to study tamoxifen-stimulated drug resistance in vivo. However, unlike MCF-7 cells, T47D cells express mutant p53 protein and lose the estrogen receptor (ER) during long-term estrogen deprivation in vitro [Pink et al., Br. J. Cancer, 74: 1227-1236, 1996 (erratum, Br. J. Cancer, 75: 1557, 1997)]. As a result, T47D tumors may respond differently from MCF-7 tumors to long-term tamoxifen treatment. Ovariectomized athymic mice were given injections bilaterally with T47D cells (5 x 10(5)) into the mammary fat pads. A rapidly growing estradiol responsive tumor (T47D:E2) was established and 0.5 mg of tamoxifen given daily blocked estrogen-stimulated growth. In subsequent experiments, low doses of tamoxifen (0.17 mg or 0.5 mg) did not produce tamoxifen-stimulated tumors at 14 weeks, whereas high-dose tamoxifen (1.5 mg) consistently produced tamoxifen-stimulated tumors (T47D:Tam; 17 tumors/20 sites) at 8 weeks. In contrast, 1.5 mg of tamoxifen produced tamoxifen-stimulated MCF-7 tumors (MCF-7: Tam2) at a slower rate (20 weeks) and less consistently (14 tumors/26 sites). When the T47D:Tam tumor was passaged, it grew maximally with either 1.5 mg of tamoxifen or a 1-cm estradiol (premenopausal levels) capsule, and similar results were obtained with MCF-7:Tam2 tumors. Interestingly, when T47D:Tam tumors were treated with the 0.5 mg of tamoxifen, tumors grew only to 50% maximum. All of the tumors originating from MCF-7 and T47D cells expressed ER at similar levels; therefore, tamoxifen did not select for an ER-negative tumor. In conclusion, we have shown that tamoxifen-stimulated T47D p53 mutant tumors can be developed rapidly with high-dose therapy (1.5 mg daily). The results from this model provide new opportunities to investigate the rapid development of drug resistance to adjuvant tamoxifen in patients with mutant p53 breast tumors.