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

Oncogene volume 31, pages 5073–5080 (2012)Cite this article

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Abstract

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.

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Acknowledgements

We thank W Lee Kraus for expression constructs and Jonathan Backer for help with kinase assays. We are especially grateful to Matthew Gamble and members of his laboratory for assistance and guidance with ChIP assays. We also like to acknowledge Antonio Di Cristofano for scientific generosity and help with animal experiments. We also thank Fannie F Seligman, Faygel Beren and Miriam Ciner for technical assistance. This work was founded by grants to MKH from NIH (CA151112), Atol Charitable Trust, Wendy Will Case Cancer Fund and Yeshiva University. TNS, ENH, ASS and HAU received support from the S Daniel Abraham Honors Program of Yeshiva University.

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Authors and Affiliations

  1. Department of Biology, Stern College for Women of Yeshiva University, New York, NY, USA

    D M Maruani, T N Spiegel, E N Harris, A S Shachter, H A Unger & M K Holz

  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    S Herrero-González

  3. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    M K Holz

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  1. D M Maruani
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Correspondence to M K Holz.

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Maruani, D., Spiegel, T., Harris, E. et al. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene 31, 5073–5080 (2012). https://doi.org/10.1038/onc.2011.657

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