Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD 21201, USA.
Clin Breast Cancer. 2010 Feb;10(1):E6-E15. doi: 10.3816/CBC.2010.n.014.
We developed a mouse model system that mimics hormone-dependent postmenopausal breast cancer. In this model, human estrogen receptor-positive (ER+) breast cancer cells (MCF-7) stably transfected with aromatase (MCF-7Ca) are grown as tumors in ovariectomized female nude mice. Using this model, we have established that aromatase inhibitors (AIs) such as letrozole and anastrozole that reduce estrogen production are more effective than the antiestrogen agent tamoxifen. This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. Nevertheless, resistance to treatment might eventually occur.
To investigate the mechanisms involved in the loss of sensitivity of the tumors to AIs, we developed a cell line isolated from the tumors of long-term letrozole-treated MCF-7Ca xenografts. This cell line was designated LTLT-Ca.
These cells exhibited lower expression of ERalpha and apparent "estradiol-independent" growth along with hyperactivation of growth factor receptor- mediated signaling pathways such as HER2/mitogen-activated protein kinase. The inhibition of HER2 with trastuzumab results in restoration of ERalpha and response to letrozole.
Our data suggest that inhibition of both the HER2 and estrogen signaling pathways is required to prolong the responsiveness of the tumors to endocrine therapies. In addition, we have shown that HER2 upregulation is an adaptive process that the tumors undergo during continued letrozole treatment, which is reversed upon removal of the treatment. The tumors regain responsiveness to letrozole after a short period "off" treatment. These studies suggest that by reversing the resistance to hormone therapy, patients could have a second response and could delay the need for chemotherapy.
我们开发了一种模拟激素依赖性绝经后乳腺癌的小鼠模型系统。在该模型中，稳定转染芳香酶的人雌激素受体阳性（ER+）乳腺癌细胞（MCF-7）在去卵巢裸鼠中生长为肿瘤。使用该模型，我们已经证实，降低雌激素生成的芳香酶抑制剂（AIs），如来曲唑和阿那曲唑，比抗雌激素药物他莫昔芬更有效。这种肿瘤内芳香酶异种移植模型已被证明能够准确预测几项临床试验的结果。然而，治疗耐药性最终可能会发生。
为了研究肿瘤对 AIs 敏感性丧失的相关机制，我们从长期接受来曲唑治疗的 MCF-7Ca 异种移植肿瘤中分离出一个细胞系。该细胞系被命名为 LTLT-Ca。
这些细胞表现出 ERalpha 表达降低和明显的“雌激素非依赖性”生长，同时 HER2/丝裂原活化蛋白激酶等生长因子受体介导的信号通路过度激活。用曲妥珠单抗抑制 HER2 可恢复 ERalpha 的表达并使肿瘤对来曲唑产生反应。
我们的数据表明，抑制 HER2 和雌激素信号通路都需要延长肿瘤对内分泌治疗的反应性。此外，我们已经表明，HER2 的上调是肿瘤在持续来曲唑治疗过程中经历的一种适应性过程，这种上调在停止治疗后会逆转。在经过短暂的停药期后，肿瘤对来曲唑的反应性会恢复。这些研究表明，通过逆转对激素治疗的耐药性，患者可以获得第二次反应，并可以延迟化疗的需要。
