Prevention of ER-negative breast cancer.
Prevention of ER-negative breast cancer.
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DOI：
10.1007/978-3-540-69297-3_13
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发表时间：
2009
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选择性雌激素受体调节剂（SERM）他莫昔芬和雷洛昔芬降低乳腺癌风险的成功证明，激发了人们对使用药物预防高危女性乳腺癌的极大兴趣。此外，最近的乳腺癌治疗试验结果表明，芳香化酶抑制剂在预防乳腺癌方面可能比SERM更有效。然而，虽然SERM和芳香化酶抑制剂确实可以预防许多雌激素受体（ER）阳性乳腺癌的发展，但这些药物不能预防ER阴性乳腺癌的发展。因此，迫切需要确定可以预防ER阴性乳腺癌的药物。我们已经研究了几类药物在临床前模型中预防ER阴性乳腺癌的能力的癌症预防活性。这些研究的结果表明，rexinoids（结合并激活RXR受体的类维生素A类似物）、酪氨酸激酶抑制剂（如EGFR抑制剂和阻断EGFR和HER 2/neu信号传导的双激酶抑制剂）和环氧合酶2（考克斯-2）抑制剂均能预防发生ER阴性乳腺癌的转基因小鼠中的ER阴性乳腺癌。目前正在研究的其他有前途的药物包括维生素D和维生素D类似物，激活PPAR-gamma核受体的药物和他汀类药物。这些药物中的许多目前正在早期癌症预防临床试验中进行测试，以确定它们是否会在乳腺组织中显示活性，以及它们是否安全用于没有乳腺癌的高危女性。将对这些研究的现状进行综述。预计在未来，有效预防ER阴性乳腺癌的药物将与激素药物（如SERM或芳香酶抑制剂）联合使用，以预防所有形式的乳腺癌。
The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer.