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The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis

Oncogene volume 29, pages 5883–5894 (2010)Cite this article

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Abstract

The Pak4 serine/threonine kinase is highly expressed in many cancer cell lines and human tumors. Although several studies have addressed the role for Pak4 in transformation of fibroblasts, most human cancers are epithelial in origin. Epithelial cancers are associated not only with changes in cell growth but also with changes in the cellular organization within the three-dimensional (3D) architecture of the affected tissues. In this study we used immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the role for Pak4 in mammary tumorigenesis. iMMECs are an excellent model system for studying breast cancer, as they can grow in 3D-epithelial cell culture, in which they form acinar structures that recapitulate in vivo mammary morphogenesis. Although Pak4 is expressed at low levels in wild-type iMMECs, it is overexpressed in response to oncogenes, such as oncogenic Ras and Her2/neu. In this study we found that overexpression of Pak4 in iMMECs leads to changes in 3D acinar architecture that are consistent with oncogenic transformation. These include decreased central acinar cell death, abrogation of lumen formation, cell polarity alterations and deregulation of acinar size and cell number. Furthermore, iMMECs overexpressing Pak4 form tumors when implanted into the fat pads of athymic mice. Our results suggest that overexpression of Pak4 triggers events that are important for the transformation of mammary epithelial cells. This is likely to be owing to the ability of Pak4 to inhibit apoptosis and promote cell survival and thus subsequent uncontrolled proliferation, and to its ability to deregulate cell shape and polarity.

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Acknowledgements

We thank Dr Chung S Yang and Dr Zhihong Yang for providing human colon cancer cell lines. This work was supported by R01 CA076342 to AM and R00 CA133181 to VK.

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  1. Y Liu and N Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Y Liu, X Cui, X Zheng & A Minden

  2. Department of Medicine, The Cancer Institute of New Jersey, New Brunswick, NJ, USA

    N Chen, S Price & V Karantza

  3. Division of Medical Oncology, Department of Internal Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA

    N Chen & V Karantza

  4. Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    L Deng

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  1. Y Liu
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Correspondence to A Minden.

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Liu, Y., Chen, N., Cui, X. et al. The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis. Oncogene 29, 5883–5894 (2010). https://doi.org/10.1038/onc.2010.329

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