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Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis

Oncogene volume 34, pages 4635–4646 (2015)Cite this article

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Abstract

Most deaths from breast cancer are caused by metastasis, a complex behavior of cancer cells involving migration, invasion, survival and microenvironment manipulation. Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) regulates focal adhesion assembly and its phosphorylation at Y639 is critical for cell migration induced by EGF. However, the role of this lipid kinase in tumor metastasis remains unclear. Here we report that PIPKIγ is vital for breast cancer metastasis. Y639 of PIPKIγ can be phosphorylated by stimulation of EGF and hepatocyte growth factor (HGF), two promoting factors for breast cancer progression. Histological analysis revealed elevated Y639 phosphorylation of PIPKIγ in invasive ductal carcinoma lesions and suggested a positive correlation with tumor grade. Orthotopically transplanted PIPKIγ-depleted breast cancer cells showed substantially reduced growth and metastasis, as well as suppressed expression of multiple genes related to cell migration and microenvironment manipulation. Re-expression of wild-type PIPKIγ in PIPKIγ-depleted cells restored tumor growth and metastasis, reinforcing the importance of PIPKIγ in breast cancer progression. Y639-to-F or a kinase-dead mutant of PIPKIγ could not recover the diminished metastasis in PIPKIγ-depleted cancer cells, suggesting that Y639 phosphorylation and lipid kinase activity are both required for development of metastasis. Further analysis with in vitro assays indicated that depleting PIPKIγ inhibited cell proliferation, MMP9 secretion and cell migration and invasion, lending molecular mechanisms for the eliminated cancer progression. These results suggest that PIPKIγ, downstream of EGF and/or HGF receptor, participates in breast cancer progression from multiple aspects and deserves further studies to explore its potential as a therapeutic target.

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Acknowledgements

We thank Dr Daniel Visscher (Mayo Clinic) for scoring the breast cancer tissue microarrays, Dr Wilma Lingle (Mayo Clinic) for providing human breast cancer tissue samples and tissue microarrays, Dr Vijayalakshmi Shridhar (Mayo Clinic) for sharing the 4T1 cells and Dr Kah Whye Peng (Mayo Clinic) for providing the luciferase system. This work was supported by research grants from the National Cancer Institute (1R01CA149039-01A1) and Susan G Komen for the Cure (KG100902).

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Author notes

  1. C Chen, X Wang and X Xiong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA,

    C Chen, Y Huang, Q Xu, J Hu & K Ling

  2. Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA,

    X Wang

  3. Peggy and Charles Stephenson Cancer Center, Oklahoma University Medicine, Oklahoma City, OK, USA

    X Xiong

  4. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Q Liu & G Ge

  5. Department of Hypertension and Nephrology, Mayo Clinic, Rochester, MN, USA,

    J Hu

  6. Cancer Center, College of Medicine, Mayo Clinic, Rochester, MN, USA

    K Ling

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Correspondence to K Ling.

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Chen, C., Wang, X., Xiong, X. et al. Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis. Oncogene 34, 4635–4646 (2015). https://doi.org/10.1038/onc.2014.393

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