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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Tamoxifen-stimulated growth of breast cancer due to p21 loss
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Tamoxifen-stimulated growth of breast cancer due to p21 loss

机译：三苯氧胺（p21）丢失导致他莫昔芬刺激乳腺癌的生长

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摘要

Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphory-lation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.
机译：他莫昔芬被广泛用于激素反应性乳腺癌的治疗。但是，某些耐药的乳腺癌会对该药产生生长增殖反应，如停药后肿瘤消退所证明。为了阐明这种悖论的分子介质，分析了他莫昔芬刺激的乳腺癌患者的组织样本。这些研究表明，细胞周期蛋白依赖性激酶抑制剂p21的缺失与他莫昔芬诱导生长的表型有关。然后产生具有p21基因体细胞缺失的永生化人乳腺上皮细胞，并显示出对他莫昔芬的生长增殖反应，而p21野生型细胞在他莫昔芬暴露后表现出生长抑制作用。突变和生化分析表明，p21细胞周期蛋白依赖性激酶抑制特性的丧失导致雌激素受体α的磷酸化过高，随后雌激素受体调节基因的基因表达增加。这些数据揭示了他莫昔芬抗药性的以前未知的分子机制，并且对他莫昔芬抗药性乳腺癌的治疗具有潜在的临床意义。

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