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The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RARβ signaling pathways in breast cancer cells

Oncogene volume 18, pages 6725–6732 (1999)Cite this article

Abstract

Retinoic acid receptor-β (RARβ) and signal transducer and activator of transcription 1 (STAT1) are important mediators of the antiproliferative and apoptotic actions of retinoids and cytokines/growth factors, respectively. Expression of both RARβ and STAT1 is lost in most breast cancer cell lines but it can be induced by retinoids in estrogen receptor-positive cells. We investigated a possible functional connection between these two mediators and present evidence supporting RARβ as a tumor suppressor. First, by using different receptor-selective retinoids, we demonstrated that RARβ induction in MCF-7 cells by all-trans-retinoic acid (atRA) was associated with the activation of STAT1 gene transcription. The direct involvement of RARβ in atRA-induced STAT1 gene activation was further demonstrated by showing that transfection with an anti-sense RARβ construct blocked atRA-induced STAT1 expression in MCF-7 cells whereas introduction of a sense-RARβ construct resulted in STAT1 induction by atRA in MDA-MB 231 cells. In addition, we showed that STAT1 was phosphorylated/activated under atRA treatment of MCF-7 cells; this process required the involvement of RARβ and protein synthesis. STAT1 phosphorylation/activation was accompanied by increased tyrosine kinase activity that was not due to the activation of JAK1, JAK2 or Tyk 2, suggesting the possible involvement of an unidentified tyrosine kinase.

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Acknowledgements

The authors are indebted to Drs R M Evans (Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA), X-K Zhang (La Jolla Cancer Research Center, La Jolla, CA, USA) and J E Darnell, Jr (Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY, USA) for providing plasmid constructs used in this experiment. We also thank Anne Gibson for technical assistance and Joanne Balmer Green for helping with manuscript preparation. This work was supported by grants from the National Institutes of Health (R01-HD32500 to MH Green) and the Pennsylvania State University Agricultural Experiment Station (to CR Baumrucker).

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  1. Nutrition Department, The Pennsylvania State University, University Park, 16802, Pennsylvania, PA, USA

    Yongfeng Shang & Michael H Green

  2. Department of Dairy and Animal Science, The Pennsylvania State University, University Park, 16802, Pennsylvania, PA, USA

    Craig R Baumrucker

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  1. Yongfeng Shang
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Shang, Y., Baumrucker, C. & Green, M. The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RARβ signaling pathways in breast cancer cells. Oncogene 18, 6725–6732 (1999). https://doi.org/10.1038/sj.onc.1203084

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