Inhibition of prolactin (PRL)-induced proliferative signals in breast cancer cells by a molecular mimic of phosphorylated PRL, S179D-PRL.

Inhibition of prolactin (PRL)-induced proliferative signals in breast cancer cells by a molecular mimic of phosphorylated PRL, S179D-PRL.
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DOI：
10.1210/en.2003-0826
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发表时间：
2003-12
期刊：
Endocrinology
影响因子：
4.8
通讯作者：
M. Schroeder;J. L. Brockman;A. Walker;L. Schuler
M. Schroeder;J. L. Brockman;A. Walker;L. Schuler
中科院分区：
医学2区
文献类型：
--
作者：
M. Schroeder;J. L. Brockman;A. Walker;L. Schuler

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催乳素 (PRL) 的翻译后修饰（包括磷酸化）随生理状态变化并改变生物活性。鉴于越来越多的证据表明 PRL 在乳腺癌增殖中的作用，我们检查了磷酸化人 PRL 的模拟物 S179D-PRL 单独或与未修饰的 PRL 组合启动乳腺肿瘤细胞中多个通路信号的能力。未修饰的 PRL 采用多种途径来增加 PRL 缺陷的 MCF-7 细胞中的细胞增殖和细胞周期蛋白 D1 水平。与未修饰的 PRL 相比，S179D-PRL 在细胞增殖、细胞周期蛋白 D1 水平以及信号转导子和转录 5 和 ERK 激活剂的磷酸化方面是弱激动剂。然而，S179D-PRL 是未修饰 PRL 对这些终点的有效拮抗剂。与未修饰的 PRL 孵育 3 天后观察到的 PRL 受体长亚型水平降低相反，S179D-PRL 上调该亚型的表达 4 倍。这些研究支持该突变体作为乳腺上皮细胞增殖信号的 PRL 拮抗剂的用途，包括在乳腺癌治疗中的潜在作用。
Posttranslational modifications of prolactin (PRL), including phosphorylation, vary with physiologic state and alter biologic activity. In light of the growing evidence for a role for PRL in proliferation in mammary cancer, we examined the ability of a mimic of phosphorylated human PRL, S179D-PRL, to initiate signals to several pathways in mammary tumor cells alone and in combination with unmodified PRL. Unmodified PRL employed multiple pathways to increase cellular proliferation and cyclin D1 levels in PRL-deficient MCF-7 cells. S179D-PRL was a weak agonist compared with unmodified PRL with regard to cellular proliferation, cyclin D1 levels, and phosphorylation of signal transducer and activator of transcription 5 and ERKs. However, S179D-PRL was a potent antagonist of unmodified PRL to these endpoints. In contrast to the reduced levels of the long isoform of the PRL receptor observed in response to a 3-d incubation with unmodified PRL, S179D-PRL up-regulated expression of this isoform, 4-fold. These studies support the utility of this mutant as a PRL antagonist to proliferative signals in mammary epithelial cells, including a potential role in breast cancer therapeutics.