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Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells

Oncogene volume 28, pages 1421–1431 (2009)Cite this article

Abstract

Basal-like breast cancers (BLBCs) are aggressive tumors with high relapse rates and poor survival. We recently reported that >70% of primary BLBCs express the oncogenic transcription/translation factor Y-box binding protein-1 (YB-1) and silencing it with small interfering RNAs (siRNAs) attenuates the growth of BLBC cell lines. To understand the basis of these earlier findings, we profiled YB-1:DNA complexes by chromatin immunoprecipitation (ChIP)-on-chip. Several tumor growth-promoting genes such as MET, CD44, CD49f, WNT and NOTCH family members were identified. In addition, YB-1 and MET are coordinately expressed in BLBC cell lines, as well as in normal human mammary progenitor cells. MET was confirmed to be a YB-1 target through traditional ChIP and gel-shift assays. More specifically, YB-1 binds to −1018 bp on the MET promoter. Silencing YB-1 with siRNA decreased MET promoter activity, transcripts, as well as protein levels and signaling. Conversely, expressing wild-type YB-1 or a constitutively active mutant YB-1 (D102) increased MET expression. Finally, silencing YB-1 or MET attenuated anchorage-independent growth of BLBC cell lines. Together, these findings implicate MET as a target of YB-1 that work in concert to promote BLBC growth.

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Abbreviations

BLBC:

basal-like breast cancer

ChIP:

chromatin immunoprecipitation

COC:

ChIP-on-chip

CST:

Cell Signaling Technologies

EMSA:

electrophoretic mobility shift assay

HGF:

hepatocyte growth factor

siRNA:

small interfering RNA

PBS:

phosphate-buffered saline

YB-1:

Y-box binding protein-1

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Acknowledgements

This project was funded by the Canadian Breast Cancer Research Alliance (awarded to SED) and the National Institute of Health (RO1 awarded to SED). A Astanehe, K To and A Davies are recipients of Michael Smith Foundation for Health Research Graduate Studentships. A Astanehe and K To are recipients of Canadian Institute for Health Graduate Studentships. A Stratford holds a Canadian Breast Cancer Foundation Postdoctoral Fellowship. P Eirew is the recipient of the US Department of Defense Breast Cancer Research Program Studentship, the Terry Fox Foundation Research Studentship from the National Cancer Institute of Canada, the Canadian Imperial Bank of Commerce Interdisciplinary Award and the Canadian Stem Cell Network Studentship.

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Author notes

  1. M R Finkbeiner and A Astanehe: These authors contributed equally to this work.

Authors and Affiliations

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

    M R Finkbeiner, A Astanehe, K To, A Fotovati, A H Davies, Y Zhao, H Jiang, A L Stratford & S E Dunn

  2. Cancer Genetics and Developmental Biology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    A Shadeo

  3. Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, Italy

    C Boccaccio & P Comoglio

  4. Division of Nephrology and Clinical Immunology, University Hospital Aachen, Aachen, Germany

    P R Mertens

  5. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    P Eirew, A Raouf & C J Eaves

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  1. M R Finkbeiner
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Correspondence to S E Dunn.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Finkbeiner, M., Astanehe, A., To, K. et al. Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells. Oncogene 28, 1421–1431 (2009). https://doi.org/10.1038/onc.2008.485

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