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PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model

Oncogene volume 35, pages 3314–3323 (2016)Cite this article

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Abstract

Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal–regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor.

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Acknowledgements

We thank Dr Dario R Alessi (University of Dundee) for sharing the PDK1fl/fl mice. This work was supported by grants to Dr Zhongjun Dong’s laboratory from Natural Science Foundation of China (81322041, 81273198, 81361128016 and 81471523), Minister of Science and Technology of China (2013CB944901) and Beijing Natural Science Foundation (5132018). Juan Du and Meixiang Yang were supported by Postdoctoral Foundation at Tsinghua-Peking Center for Life Sciences.

Author contributions

Juan Du, Meixiang Yang, Shasha Chen and Dan Li performed and analyzed the experiments; Zai Chang provided critical reagents and advice; Juan Du, Meixiang Yang and Zhongjun Dong conceived the research, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. School of Medicine, Tsinghua University, Beijing, China

    J Du, M Yang, S Chen, D Li & Z Dong

  2. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China

    S Chen

  3. Center of Animal Facility, Tsinghua University, Beijing, China

    Z Chang

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  1. J Du
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Correspondence to Z Dong.

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Du, J., Yang, M., Chen, S. et al. PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model. Oncogene 35, 3314–3323 (2016). https://doi.org/10.1038/onc.2015.393

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