Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation

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) a 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 ER alpha, while ERa upregulates S6K1 expression. This S6K1-ER alpha relationship creates a positive feed-forward loop in control of breast cancer cell proliferation. Furthermore, the co-dependent association between S6K1 and ER alpha may be exploited in the development of targeted breast cancer therapies. Oncogene (2012) 31, 5073-5080; doi:10.1038/onc.2011.657; published online 30 January 2012