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Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth

Oncogene volume 21, pages 7680–7689 (2002)Cite this article

Abstract

AP-1 transcription factors play a critical role in signal transduction pathways in many cells. We have investigated the role of AP-1 in controlling proliferative signals in breast cells, and have previously shown that AP-1 complexes are activated by peptide and steroid growth factors in both normal and malignant breast cells. In this study, we investigated the role of AP-1 in transducing proliferative signals induced by peptide and steroid growth factors. We used MCF-7 clones that express a specific inhibitor of AP-1, a dominant-negative cJun mutant (TAM67), under the control of an inducible promoter to investigate the role of AP-1 in regulating breast cancer growth. In the presence of doxycycline (Dox), the AP-1 inhibitor was not expressed, and the MCF-7 clones proliferated normally in response to serum stimulation. However, when Dox was withdrawn, TAM67 was expressed, AP-1 activity was inhibited, and serum-induced proliferation was blocked. We next investigated whether the mitogenic response to specific growth factors also requires AP-1. MCF-7 Tet-Off-TAM67 cells were grown in the presence of increasing concentrations of IGF-1, EGF, heregulin-β, bFGF, or estrogen under un-induced and induced conditions. These studies showed that the AP-1 inhibitor completely blocked proliferation in response to the peptide growth factors (IGF-1, EGF, heregulin-β, and bFGF), and partially blocked the response to estrogen. To investigate the effect of AP-1 blockade on in vivo tumor growth, we injected the MCF-7 Tet-Off TAM67 cells into nude mice receiving doxycycline to suppress the expression of the AP-1 inhibitor. After the mice developed tumors, they were randomized to either continue to receive Dox or not. In mice not receiving Dox, the expression of TAM67 was induced, and tumor growth was inhibited, while the tumors in mice receiving Dox continued to grow. Analysis of the tumors from these mice showed that the expression of TAM67 caused reduced proliferation of the breast cancer cells without inducing apoptosis. These results demonstrate that AP-1 blockade supresses mitogenic signals from multiple different peptide growth factors as well as estrogen, and inhibits the growth of MCF-7 breast cancer cells both in vitro and in vivo. These results suggest that novel agents specifically targeting AP-1 or its activating kinases could be promising agents for the treatment of breast cancer.

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Abbreviations

AP-1:

activating protein-1

TAM-67:

cJun Dominant-negative mutant

Dox:

doxycycline

ER:

estrogen receptor

ERE:

estrogen response element

EGF:

epidermal growth factor

IGF:

insulin-like growth factor

TGF-α:

transforming growth factor-α

TPA:

12-O-tetradecanoylphorbol-13-acetate

bFGF:

Basic fibroblast growth factor

HRG-β:

Heregulin-beta

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Acknowledgements

We thank Drs Steffi Oesterreich, Adrian Lee, and Kendall Wu for their helpful discussions and critical reading of the manuscript, Drs Craig Allred and Syed Mohsin for their assistance with preparation of the figures, and Ms Linda Kimbrough for her assistance in preparing the manuscript. This work was supported by the Department of Defense grant (DAMD-17-96-1-6225 to PH Brown), the Department of Defense Postdoctoral Fellowship Award (BC-000322 to Y Liu), and the National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant (CA 58183 to CK Osborne.)

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Authors and Affiliations

  1. Department of Medicine, Breast Center, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Yongmin Liu, Yun Zhang, Hee-Tae Kim, Chunhua Lu, Gouqing Ge, Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne & Powel H Brown

  2. Department of Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne & Powel H Brown

  3. The University of Texas Health Science Center at San Antonio, San Antonio, 78284, Texas, TX, USA

    John Ludes-Meyers & Debbie Munoz-Medellin

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  1. Yongmin Liu
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  2. John Ludes-Meyers
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Correspondence to Powel H Brown.

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Liu, Y., Ludes-Meyers, J., Zhang, Y. et al. Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene 21, 7680–7689 (2002). https://doi.org/10.1038/sj.onc.1205883

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