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首页> 外文期刊>Oncogene >Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation
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Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation

机译：Wilms的肿瘤蛋白1：T-47D乳腺癌细胞中孕激素调节的早期靶标，可调节增殖和分化

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Progesterone regulates the proliferation and differentiation of normal mammary epithelium. In breast cancer cells, progesterone and its synthetic analogs, progestins, induce long-term growth inhibition and differentiation. However, the mechanisms responsible are not fully understood. When T-47D breast cancer cells were treated with the synthetic progestin ORG 2058 (16α-ethoxy-21-hydroxy-19-norpregn-4-en-3,20-dione), all isoforms of Wilms' tumor protein 1 (Wt1) mRNA and protein were rapidly downregulated. We reasoned that the decrease in Wt1 levels may contribute to the long-term antiproliferative and differentiative effects of progestins as proliferation and differentiation are known end points of Wt1 action. Consistent with this idea, Wt1 small interfering RNA led to a decrease in S?phase and cyclin D1 levels, and increased Oil-Red-O staining, indicating increased lipogenesis. Conversely, overexpression of Wt1 attenuated the decrease in S?phase induced by ORG 2058 at 48–96?h. This was accompanied by the sustained expression of cyclin D1 despite progestin treatment, and increased levels of retinoblastoma (Rb) phosphorylation at sites targeted by cyclin D1-Cdk4 (Ser249/Thr252). Wt1 overexpression also attenuated the ORG 2058-mediated increase in fatty acid synthase levels and reduced lipogenesis. Thus, Wt1 downregulation was sufficient to mimic the effects of progestin and was necessary for complete progestin-mediated proliferative arrest and subsequent differentiation. Furthermore, Wt1 overexpression modulated the effects of progestins but not anti-estrogens or androgens. These results indicate that Wt1 is an important early target of progestins that regulates both proliferation and differentiation in breast cancer cells.
机译：孕酮调节正常乳腺上皮的增殖和分化。在乳腺癌细胞中，孕酮及其合成类似物孕激素诱导长期生长抑制和分化。但是，尚未完全了解负责机制。当用合成孕激素ORG 2058（16α-乙氧基-21-羟基-19-norpregn-4-en-3,20-dione）处理T-47D乳腺癌细胞时，Wilms肿瘤蛋白1（Wt1）的所有同工型mRNA和蛋白质迅速下调。我们认为Wt1水平的降低可能有助于孕激素的长期抗增殖和分化作用，因为增殖和分化是Wt1作用的已知终点。与这个想法一致的是，Wt1小分子干扰RNA导致S期和细胞周期蛋白D1水平降低，并且油红Red O染色增加，表明脂肪形成增加。相反，Wt1的过表达减弱了ORG 2058在48–96？h诱导的S？期下降。尽管进行了孕激素治疗，但伴随着细胞周期蛋白D1的持续表达，并在细胞周期蛋白D1-Cdk4（Ser249 / Thr252）靶向的部位增加了视网膜母细胞瘤（Rb）磷酸化水平。 Wt1过表达也减弱了ORG 2058介导的脂肪酸合酶水平增加和脂肪生成减少。因此，Wt1的下调足以模拟孕激素的作用，对于完全由孕激素介导的增殖停滞和随后的分化是必需的。此外，Wt1的过表达调节了孕激素的作用，但没有调节抗雌激素或雄激素的作用。这些结果表明，Wt1是孕激素的重要早期靶标，它可调节乳腺癌细胞的增殖和分化。

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