Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer

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Abstract

Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.

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Figure 1: Discovery of the MAST kinase and Notch gene fusions in breast cancer identified by paired-end transcriptome sequencing.
Figure 2: Characterization of MAST fusion genes.
Figure 3: Identification and characterization of Notch gene aberrations in breast carcinomas.
Figure 4: γ-secretase inhibitor DAPT effects in fusion positive and negative breast carcinoma cell lines.

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Acknowledgements

We thank R. Morey for high-throughput sequencing support; T. Barrette for hardware and database management; R. Wang, N. Consul, C. Malla, L. Ma, J. Milton, L. Cai and M. Mei for technical help; and K. Suleman and W. Yan for help with cytogenetic analysis. D. Appledorn from Essen Bioscience performed the IncuCyte analyses. The aims of this project were defined by the Department of Defense Breast Cancer Research Program (W81XWH-08-0110) to A.M.C. This project was supported in part by an American Association for Cancer Research Stand Up to Cancer (SU2C) award to A.M.C. and J.S.R.-F., grant R01 CA125577 to C.G.K. The National Functional Genomics Center (W81XWH-11-1-0520), which is supported by the Department of Defense (A.M.C.) and, in part, by the US National Institutes of Health through the University of Michigan's Cancer Center Support grant 5 P30 CA46592. A.M.C. is supported by the US National Cancer Institute's Early Detection Research Network (U01 CA111275), the Doris Duke Charitable Foundation Clinical Scientist Award and the Burroughs Welcome Foundation Award in Clinical Translational Research. R.N., M.B.L. and J.S.R.-F. are funded in part by Breakthrough Breast Cancer. A.M.C. is an American Cancer Society Research professor and Taubman Scholar. C.K.S. and A.M.C. share senior authorship.

Author information

D.R.R., C.K.-S. and A.M.C. conceived of the experiments. D.R.R., C.K.-S., Y.-M.W. and X.C. performed transcriptome sequencing. D.R.R., Y.-M.W. and X.C. performed target capture screening and sequencing. S.K.-S., C.A.M. and M.I. performed the bioinformatics analysis of high-throughput sequencing data and the nomination of gene fusions. C.S.G., R.J.L. and M.Q. performed bioinformatic analysis of high-throughput sequencing data for the gene expression profiling. C.K.-S., D.R.R. and Y.-M.W. performed the gene fusion validations. S.S. performed the in vitro experiments of MAST. I.A.A. performed the chorioallantoic membrane assays. B.A. performed the xenograft experiments. D.R.R. and Y.-M.W. performed the in vitro experiments of Notch. X.J. performed the microarray experiments. J.S., M.S.S., C.G.K., T.J.G., N.P., R.N., M.B.L. and J.S.R.-F. provided breast cancer tissue samples and the associated clinical annotation. N.P. performed fluorescence in situ hybridization experiments, and R.M. evaluated the fluorescence in situ hybridization results. D.R.R., C.K.-S. and A.M.C. wrote the manuscript, which was reviewed by all authors.

Correspondence to Chandan Kumar-Sinha or Arul M Chinnaiyan.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–4 and Supplementary Tables 1–3 (PDF 2288 kb)

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