Brodie Angela, Jelovac Danijela, Macedo Luciana, Sabnis Gauri, Tilghman Syreeta, Goloubeva Olga
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):884s-8s.
In previous studies using a xenograft model with tumors of human estrogen receptor (ER)-positive breast cancer cells transfected with aromatase (MCF-7Ca), we explored the antitumor efficacy of treatment combining the nonsteroidal aromatase inhibitor letrozole with tamoxifen. However, treatment with this combination resulted in tumor suppression similar to tamoxifen alone but was less effective than letrozole alone. Clinical findings with the nonsteroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although letrozole was the most effective single agent in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapted to growth during letrozole treatment, we determined the expression of proteins in tumors during letrozole treatment compared with the tumors of control mice. We found that tumors initially up-regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the mitogen-activated protein kinase cascade (p-Raf, p-MEK1/2, and p-MAPK) but not Akt were increased in tumors no longer responsive to letrozole. The results suggest that tumor cells adapt to estrogen deprivation during letrozole treatment by activation of alternate signaling pathways. When letrozole was combined with the pure antiestrogen fulvestrant, which down-regulates ER, the combination was extremely effective. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Thus, achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.
在先前使用异种移植模型的研究中，我们将人雌激素受体（ER）阳性乳腺癌细胞转染芳香化酶（MCF-7Ca）形成肿瘤，探讨了非甾体芳香化酶抑制剂来曲唑与他莫昔芬联合治疗的抗肿瘤疗效。然而，这种联合治疗导致的肿瘤抑制效果与单独使用他莫昔芬相似，但不如单独使用来曲唑有效。非甾体抑制剂阿那曲唑与他莫昔芬联合使用的临床研究结果（ATAC试验）与我们的结果一致。尽管来曲唑在该模型中是最有效的单一药物，但在持续治疗期间肿瘤最终开始生长。为了研究肿瘤在来曲唑治疗期间适应生长的机制，我们测定了来曲唑治疗期间肿瘤中蛋白质的表达，并与对照小鼠的肿瘤进行比较。我们发现，肿瘤最初会上调ER，但随后对来曲唑无反应的肿瘤中受体水平下降。在对来曲唑不再有反应的肿瘤中，衔接蛋白（p-Shc和Grb-2）以及丝裂原活化蛋白激酶级联反应中的所有信号蛋白（p-Raf、p-MEK1/2和p-MAPK）均增加，但Akt未增加。结果表明，肿瘤细胞在来曲唑治疗期间通过激活替代信号通路来适应雌激素剥夺。当来曲唑与下调ER的纯抗雌激素氟维司群联合使用时，这种联合治疗极其有效。肿瘤缩小了45%，并在实验持续时间（29周）内保持无生长状态。因此，实现更完全的雌激素阻断可能会延迟调节增殖的激素非依赖性信号通路的发展。
