Department of Biology, Stern College for Women of Yeshiva University, New York, NY, USA.
Oncogene. 2012 Dec 6;31(49):5073-80. doi: 10.1038/onc.2011.657. Epub 2012 Jan 30.
The 40S ribosomal S6 kinase 1 (S6K1) is an important regulator of cell growth. Expression of S6K1 is often elevated in breast cancer cells. However, the transcriptional mechanism of S6K1 overexpression is not understood. In this report, we demonstrate that estrogen activates expression of S6K1 via estrogen receptor (ER)α in ER-positive breast cancer cells. We also show that estrogen acts on the proximal promoter of the S6K1 gene in a mechanism involving the transcriptional factor GATA-3. Finally, we provide data that support the importance of estrogenic regulation of S6K1 expression in breast cancer cell proliferation. S6K1 directly phosphorylates and regulates ligand-independent activity of ERα, while ERα upregulates S6K1 expression. This S6K1-ERα relationship creates a positive feed-forward loop in control of breast cancer cell proliferation. Furthermore, the co-dependent association between S6K1 and ERα may be exploited in the development of targeted breast cancer therapies.
40S 核糖体 S6 激酶 1（S6K1）是细胞生长的重要调节因子。S6K1 的表达在乳腺癌细胞中常常升高。然而，S6K1 过表达的转录机制尚不清楚。在本报告中，我们证明雌激素通过 ER 阳性乳腺癌细胞中的雌激素受体（ER）α激活 S6K1 的表达。我们还表明，雌激素通过涉及转录因子 GATA-3 的机制作用于 S6K1 基因的近端启动子。最后，我们提供的数据支持雌激素对 S6K1 表达在乳腺癌细胞增殖中的调节作用的重要性。S6K1 直接磷酸化并调节 ERα 的配体非依赖性活性，而 ERα 上调 S6K1 的表达。这种 S6K1-ERα 关系在控制乳腺癌细胞增殖中形成了一个正反馈回路。此外，S6K1 和 ERα 之间的协同关联可能会被利用于开发针对乳腺癌的靶向治疗方法。
