Functionally Recurrent Rearrangements of the MAST Kinase and Notch Gene Families in Breast Cancer

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nature medicine (Impact Factor: 27.36). 11/2011; 17(12):1646-51. DOI: 10.1038/nm.2580
Source: PubMed


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.

Download full-text


Available from: Chandan Kumar-Sinha
  • Source
    • "The changes of expression of these classes of genes suggest a cell cycle arrest in Shp2-deficient cells. Upregulation of Skp2, amplification of Aurka, and translocation of Notch have been detected in human breast cancers (Signoretti et al, 2002; Anand et al, 2003; Robinson et al, 2011); these genes were also implicated in senescence inhibition of different cancers such as melanoma, prostate, or colon cancer (Huck et al, 2010; Lin et al, 2010; Kang et al, 2013). Interestingly, we found that Skp2, Aurka (encoding Aurora A kinase), Dll1 (encoding a Notch ligand), and the Notch target gene Hey1 were downregulated by Shp2 ablation or inhibition (Fig 2B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer. © 2015 The Authors.
    Full-text · Article · Mar 2015 · The EMBO Journal
  • Source
    • "While recent studies have reported recurrent fusion genes in breast cancer that are the result of genomic rearrangements [13, 15, 16, 18, 34], recurrent read-through fusion transcripts in breast cancer have not been previously characterized. We performed RNA-seq [35] on 28 breast cancer cell lines to identify candidate read-through fusion transcripts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Read-through fusion transcripts that result from the splicing of two adjacent genes in the same coding orientation are a recently discovered type of chimeric RNA. We sought to determine if read-through fusion transcripts exist in breast cancer. We performed paired-end RNA-seq of 168 breast samples, including 28 breast cancer cell lines, 42 triple negative breast cancer primary tumors, 42 estrogen receptor positive (ER+) breast cancer primary tumors, and 56 non-malignant breast tissue samples. We analyzed the sequencing data to identify breast cancer associated read-through fusion transcripts. We discovered two recurrent read-through fusion transcripts that were identified in breast cancer cell lines, confirmed across breast cancer primary tumors, and were not detected in normal tissues (SCNN1A-TNFRSF1A and CTSD-IFITM10). Both fusion transcripts use canonical splice sites to join the last splice donor of the 5′ gene to the first splice acceptor of the 3′ gene, creating an in-frame fusion transcript. Western blots indicated that the fusion transcripts are translated into fusion proteins in breast cancer cells. Custom small interfering RNAs targeting the CTSD-IFITM10 fusion junction reduced expression of the fusion transcript and reduced breast cancer cell proliferation. Read-through fusion transcripts between adjacent genes with different biochemical functions represent a new type of recurrent molecular defect in breast cancer that warrant further investigation as potential biomarkers and therapeutic targets. Both breast cancer associated fusion transcripts identified in this study involve membrane proteins (SCNN1A-TNFRSF1A and CTSD-IFITM10), which raises the possibility that they could be breast cancer-specific cell surface markers. Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-3019-2) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014 · Breast Cancer Research and Treatment
  • Source
    • "Only a small number of additional molecular interactions of MAST kinases have been reported; these include interactions with Traf6, PCLKC and β2-synthrophin (Lumeng et al., 1999; Okazaki et al., 2002; Xiong et al., 2004). Despite the association of MAST kinases with diseases including inflammatory bowel disease and breast cancer (Labbé et al., 2008; Robinson et al., 2011), the physiological functions of this protein family within the developing or adult organism remain elusive. Our findings show that Dop plays a crucial role in dynein-dependent microtubule-based transport and is required for the phosphorylation of Dynein intermediate chain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cellularisation of the Drosophila syncytial blastoderm embryo into the polarised blastoderm epithelium provides an excellent model with which to determine how cortical plasma membrane asymmetry is generated during development. Many components of the molecular machinery driving cellularisation have been identified, but cell signalling events acting at the onset of membrane asymmetry are poorly understood. Here we show that mutations in drop out (dop) disturb the segregation of membrane cortical compartments and the clustering of E-cadherin into basal adherens junctions in early cellularisation. dop is required for normal furrow formation and controls the tight localisation of furrow canal proteins and the formation of F-actin foci at the incipient furrows. We show that dop encodes the single Drosophila homologue of microtubule-associated Ser/Thr (MAST) kinases. dop interacts genetically with components of the dynein/dynactin complex and promotes dynein-dependent transport in the embryo. Loss of dop function reduces phosphorylation of Dynein intermediate chain, suggesting that dop is involved in regulating cytoplasmic dynein activity through direct or indirect mechanisms. These data suggest that Dop impinges upon the initiation of furrow formation through developmental regulation of cytoplasmic dynein.
    Full-text · Article · May 2014 · Development
Show more