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YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification

Oncogene volume 30, pages 3649–3660 (2011)Cite this article

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Abstract

Y-box binding protein-1 (YB-1) expression in the mammary gland promotes breast carcinoma that demonstrates a high degree of genomic instability. In the present study, we developed a model of pre-malignancy to characterize the role of this gene during breast cancer initiation and early progression. Antibody microarray technology was used to ascertain global changes in signal transduction following the conditional expression of YB-1 in human mammary epithelial cells (HMEC). Cell cycle-associated proteins were frequently altered with the most dramatic being LIM kinase 1/2 (LIMK1/2). Consequently, the misexpression of LIMK1/2 was associated with cytokinesis failure that acted as a precursor to centrosome amplification. Detailed investigation revealed that YB-1 localized to the centrosome in a phosphorylation-dependent manner, where it complexed with pericentrin and γ-tubulin. This was found to be essential in maintaining the structural integrity and microtubule nucleation capacity of the organelle. Prolonged exposure to YB-1 led to rampant acceleration toward tumorigenesis, with the majority of cells acquiring numerical and structural chromosomal abnormalities. Slippage through the G1/S checkpoint due to overexpression of cyclin E promoted continued proliferation of these genomically compromised cells. As malignancy further progressed, we identified a subset of cells harboring HER2 amplification. Our results recognize YB-1 as a cancer susceptibility gene, with the capacity to prime cells for tumorigenesis.

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Acknowledgements

We thank Ching-Shih Chen (The Ohio State University) for providing BI-D1870 and Michel Lebel (l’Universite Laval) for providing plasmid encoding GFP-tagged YB-1. This study was supported by the National Institutes of Health RO1 CA114017 (SED, IMB), the Michael Smith Foundation for Health Research (AHD), the Canadian Institutes of Health Research (AHD, SED) and the Canadian Breast Cancer Foundation (ALS).

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Authors and Affiliations

  1. Departments of Pediatrics and Experimental Medicine, Laboratory of Oncogenomic Research, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    A H Davies, M R Pambid, K Hu, A L Stratford & S E Dunn

  2. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada

    I Barrett & P Hieter

  3. Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

    S Freeman

  4. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    I M Berquin

  5. Division of Neurology, The Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada

    S Pelech

  6. Kinexus Bioinformatics Corporation, Vancouver, British Columbia, Canada

    S Pelech

  7. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

    C Maxwell

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  1. A H Davies
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  2. I Barrett
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Correspondence to S E Dunn.

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Davies, A., Barrett, I., Pambid, M. et al. YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification. Oncogene 30, 3649–3660 (2011). https://doi.org/10.1038/onc.2011.82

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