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The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

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Abstract

Microarray expression signature analyses have suggested that extracellular matrix (ECM) gene dysregulation is predictive of metastasis in both mouse mammary tumorigenesis and human breast cancer. We have previously demonstrated that such ECM dysregulation is influenced by hereditary germline-encoded variation. To identify novel metastasis efficiency modifiers, we performed expression QTL (eQTL) mapping in recombinant inbred mice by characterizing genetic loci modulating metastasis-predictive ECM gene expression. Three reproducible eQTLs were observed on chromosomes 7, 17 and 18. Candidate genes were identified by correlation analyses and known associations with metastasis. Seven candidates were identified (Ndn, Pi16, Luc7l, Rrp1b, Brd4, Centd3 and Csf1r). Stable transfection of the highly metastatic Mvt-1 mouse mammary tumor cell line with expression vectors encoding each candidate modulated metastasis-predictive ECM gene expression. Implantation of these cells into mice demonstrated that candidate gene ectopic expression impacts tumor progression. Gene expression analyses facilitated the construction of a transcriptional network that we have termed the ‘Diasporin Pathway’. This pathway contains the seven candidates, as well as metastasis-predictive ECM genes and metastasis suppressors. Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1. Furthermore, we demonstrate that the microarray gene expression signatures induced by activation of ECM eQTL genes in the Mvt-1 cell line can be used to accurately predict survival in a human breast cancer cohort. These data imply that the Diasporin Pathway may be an important nexus in tumor progression in both mice and humans.

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Acknowledgements

We thank Drs. Doug Lowy and Jude Alsarraj for critical comments on this manuscript. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Nigel P. S. Crawford, Renard C. Walker, Luanne Lukes, Jennifer S. Officewala, Robert W. Williams & Kent W. Hunter

  2. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA

    Robert W. Williams

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  1. Nigel P. S. Crawford
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  2. Renard C. Walker
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  3. Luanne Lukes
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  4. Jennifer S. Officewala
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Correspondence to Kent W. Hunter.

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Crawford, N.P.S., Walker, R.C., Lukes, L. et al. The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival. Clin Exp Metastasis 25, 357–369 (2008). https://doi.org/10.1007/s10585-008-9146-6

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