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AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity

Oncogene volume 23, pages 8238–8246 (2004)Cite this article

Abstract

The AP-1 transcription factor is a central component of signal transduction pathways in many cells, although the exact role of AP-1 in controlling cell growth and malignant transformation is unknown. We have previously shown that AP-1 complexes are activated by peptide and steroid growth factors in both normal and malignant breast cells, and that blocking AP-1 by overexpressing a dominant-negative form of cJun (cJun-DN, TAM67) inhibits breast cancer cell growth both in vivo and in vitro. We hypothesized that TAM67 inhibits cell growth by altering the expression of cell cycle regulatory proteins, thus causing a cell cycle block. In the present study, we used clones of MCF7 breast cancer cells that express TAM67 under the control of an inducible promoter. First, we determined the effect of AP-1 blockade on cell growth, then we performed 3H-thymidine incorporation and flow cytometry assays to investigate whether TAM67 inhibits the cell cycle. We observed that in the presence of serum TAM67 inhibited cell growth and caused a block in the G1 phase of the cell cycle. Next, we performed Western-blotting and CDK kinase assays to determine the effects of TAM67 on retinoblastoma (Rb) phosphorylation, the expression of cell cycle regulatory proteins, and CDK activity. We discovered that TAM67 inhibited Rb phosphorylation and reduced E2F activity. We also found that TAM67 decreased the expression of D and E cyclins, reduced CDK2 and CDK4 activity, and increased the CDK inhibitor p27. The studies of gene expression at the RNA level showed that TAM67 decreased cyclin Ds mRNA expression. Our study suggests that in the presence of serum, TAM67 inhibits breast cancer growth predominantly by inducing inhibitors of cyclin-dependent kinases (such as p27) and by reducing the expression of the cyclins involved in transitioning from G1 into S phase of the cell cycle. These studies lay the foundation for future attempt to develop new agents for the treatment and prevention of breast cancer.

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Abbreviations

AP-1:

activating protein-1

CDK:

cyclin-dependent kinase

Dox:

doxycycline

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Acknowledgements

We thank Dr Kendall Wu, David Denardo, and Dr Gu Kong, for their helpful discussions and critical reading of the manuscript. We would also like to thank Linda Kimbrough for her assistance in preparing this manuscript. This work was supported by the Department of Defense Grant (DAMD-17-96-1-6225 to PHB) and the Department of Defense Postdoctoral Fellowship Award (BC-000322).

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Author notes

  1. Yongmin Liu

    Present address: Metabolism & Cancer Susceptibility Section, National Cancer Institute, Frederick, MD, 21702, USA

  2. Yongmin Liu and Chunhua Lu: These authors contributed equally to the work.

Authors and Affiliations

  1. Departments of Medicine and Molecular and Cellular Biology, Baylor Breast Center, Baylor College of Medicine, One Baylor Plaza, MS 600, Houston, 77030, TX, USA

    Yongmin Liu, Chunhua Lu, Qiang Shen, Heetae Kim & Powel H Brown

  2. Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, 78284, TX, USA

    Debbie Munoz-Medellin

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  1. Yongmin Liu
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Correspondence to Powel H Brown.

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Liu, Y., Lu, C., Shen, Q. et al. AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene 23, 8238–8246 (2004). https://doi.org/10.1038/sj.onc.1207889

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