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p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis

Oncogene volume 32, pages 2292–2303 (2013)Cite this article

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Abstract

Cell proliferation and invasion are critical for malignant progression, yet how these processes relate to each other and whether they regulate one another during metastasis is unknown. We show that invasiveness of breast cancer cells is associated with growth arrest due to p21CIP1 upregulation. Knockdown of p21CIP1 increases cell proliferation and suppresses invasion. Since p21CIP1 acts to inhibit cyclin E during cell-cycle progression, we demonstrated that a constitutively active form of cyclin E had similar effects to p21CIP1 inhibition resulting in enhanced cell growth and suppressed invasiveness. We tested these findings in vivo in the Polyoma middle T mammary tumor model in which p21CIP1 was deleted. p21CIP1 knockout mice exhibited dramatic suppression of metastasis, independent of tumor growth, which was rescued by p21CIP1. Metastasis suppression by p21CIP1 ablation was associated with striking cytoskeletal reorganization leading to a non-invasive and highly proliferative state. Thus, p21CIP1 regulates metastasis by mediating reciprocal switching between invasion and proliferation.

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Acknowledgements

We thank Dr Larry Herbst for his expert advice on animal studies. We thank the analytical imaging facility at AECOM for assistance with imaging. This work was supported by grants from National Cancer Institute grant (1R01 CA135061-01A1) and the Breast Cancer Research Foundation (RB Hazan). James Hulit was supported by the Susan G Komen foundation.

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Author notes

  1. X Qian and J Hulit: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

    X Qian, J Hulit, K Suyama, E A Eugenin, T J Belbin, O Loudig, J Locker & R B Hazan

  2. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    T Smirnova, Z N Zhou & J Segall

  3. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    G R Phillips

  4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    L Norton

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  1. X Qian
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Correspondence to R B Hazan.

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Qian, X., Hulit, J., Suyama, K. et al. p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis. Oncogene 32, 2292–2303 (2013). https://doi.org/10.1038/onc.2012.249

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