The Induction of KLF5 Transcription Factor by Progesterone Contributes to Progesterone-Induced Breast Cancer Cell Proliferation and Dedifferentiation
The Induction of KLF5 Transcription Factor by Progesterone Contributes to Progesterone-Induced Breast Cancer Cell Proliferation and Dedifferentiation
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DOI：
10.1210/me.2010-0497
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发表时间：
2011-07-01
影响因子：
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通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
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作者：
Liu, Rong;Zhou, Zhongmei;Chen, Ceshi
孕激素（Pg）促进怀孕和哺乳期间的正常乳房发育，并增加发生基底型浸润性乳腺癌的风险。然而，Pg的作用机制尚未完全了解。在这项研究中，我们证明了Klf 5的mRNA和蛋白质表达，乳腺癌中的促增殖转录因子，显着上调小鼠妊娠和哺乳期乳腺。Pg，而不是雌激素和催乳素，诱导Krupple-like因子5（KLF 5）在多个Pg受体（PR）阳性乳腺癌细胞系的表达。在PR阳性的T47 D乳腺癌细胞中，Pg通过PR诱导KLF 5的转录。Pg激活的PR可能通过与KLF 5启动子处的Pg反应元件结合而增加KLF 5启动子活性。重要的是，当KLF 5的诱导作用被小干扰RNA阻断时，Pg不能促进T47 D细胞的增殖。KLF 5是Pg上调细胞周期基因表达所必需的，包括CyclinA，Cdt 1和E2 F3。此外，KLF 5过表达足以诱导细胞角蛋白5（CK 5）的表达，并通过KLF 5小干扰RNA显着降低Pg的CK 5的诱导。在一组乳腺癌细胞系中，KLF 5和CK 5的表达呈正相关。综上所述，我们得出结论，KLF 5是一个前列腺素诱导的基因，有助于前列腺素介导的乳腺上皮细胞增殖和去分化。（分子内分泌学25：1137-1144，2011）
Progesterone (Pg) promotes normal breast development during pregnancy and lactation and increases the risk of developing basal-type invasive breast cancer. However, the mechanism of action of Pg has not been fully understood. In this study, we demonstrate that the mRNA and protein expression of Klf5, a pro-proliferation transcription factor in breast cancer, was dramatically up-regulated in mouse pregnant and lactating mammary glands. Pg, but not estrogen and prolactin, induced the expression of Krupple-like factor 5 (KLF5) in multiple Pg receptor (PR)positive breast cancer cell lines. Pg induced the KLF5 transcription through PR in the PR-positive T47D breast cancer cells. Pg-activated PR increased the KLF5 promoter activity likely through binding to a Pg response element at the KLF5 promoter. Importantly, Pg failed to promote T47D cell proliferation when the KLF5 induction was blocked by small interfering RNA. KLF5 is essential for Pg to up-regulate the expression of cell cycle genes, including CyclinA, Cdt1, and E2F3. In addition, KLF5 overexpression was sufficient to induce the cytokeratin 5 (CK5) expression, and the induction of CK5 by Pg was significantly reduced by KLF5 small interfering RNA. Consistently, the expression of KLF5 was positively correlated with that of CK5 in a panel of breast cancer cell lines. Taken together, we conclude that KLF5 is a Pg-induced gene that contributes to Pg-mediated breast epithelial cell proliferation and dedifferentiation. (Molecular Endocrinology 25: 1137-1144, 2011)