TrkC plays an essential role in breast tumor growth and metastasis

Jin, Wook; Kim, Gyoung Mi; Kim, Min Soo; Lim, Mi Hee; Yun, Chohee; Jeong, Joon; Nam, Jeong Seok; Kim, Seong‐Jin

doi:10.1093/carcin/bgq180

Cited by 68 publications

(88 citation statements)

References 43 publications

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“…NT-3 stimulation resulted in rapid and sustained Ras activation, which was observed in TrkC-expressing cells only (Figure 3d). These effects were consistent with previous reports demonstrating that Ras is a mediator of TrkC signaling, 6,28 and further suggested that proliferative and survival axes are activated in the absence of additional neurotrophin components (for example, TrkA, TrkB, NGFR or their ligands).…”

Section: Introductionsupporting

confidence: 92%

“…With the goal to characterize signaling pathways involved in tumor growth and invasion to enhance therapeutic insight, we performed expression analysis of macro-dissected primary ACC specimens and characterized a novel ACC marker, TrkC/NTRK3, a receptor tyrosine kinase that binds neurotrophin 3. Our interest in TrkC was further stimulated by its overexpression in cancers (for example, neuroblastoma, 4 melanoma, 5 and breast cancer 6 ), trophic stimulation by NT-3 and by the availability of small-molecule Trk inhibitors. 7 Trk receptors and neurotrophins are involved in almost all stages of nervous system development [8][9][10][11] where TrkC conveys NT-3-dependent pro-survival effects but triggers apoptosis in the absence of ligand.…”

Section: Introductionmentioning

confidence: 99%

“…25 1 Recent evidence suggests that TrkC/NT-3 signaling is linked with invasion in medulloblastoma, 26,27 melanoma 5 and breast cancer. 6,28 In addition, TrkC expression has been correlated with the invasion into venous and nervous tissues in pancreatic ductal carcinoma; 29 however, the molecular and cellular mechanisms of such activity remain unclear. To explore the cellular and molecular consequences of TrkC signaling, TrkC was ectopically expressed in cancer cells lacking expression of any neurotrophin receptors or their ligands.…”

Section: Introductionmentioning

confidence: 99%

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TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

et al. 2012

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Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neurotrophin-3 receptor TrkC/NTRK3, neural crest marker SOX10, and other neurologic genes. Here, we characterize TrkC as a novel ACC marker, which was highly expressed in 17 out of 18 ACC primary-tumor specimens, but not in mucoepidermoid salivary carcinomas or head and neck squamous cell carcinoma. Expression of the TrkC ligand NT-3 and Tyr-phosphorylation of TrkC detected in our study suggested the existence of an autocrine signaling loop in ACC with potential therapeutic significance. NT-3 stimulation of U2OS cells with ectopic TrkC expression triggered TrkC phosphorylation and resulted in Ras, Erk 1/2 and Akt activation, as well as VEGFR1 phosphorylation. Without NT-3, TrkC remained unphosphorylated, stimulated accumulation of phospho-p53 and had opposite effects on p-Akt and p-Erk 1/2. NT-3 promoted motility, migration, invasion, soft-agar colony growth and cytoskeleton restructuring in TrkC-expressing U2OS cells. Immunohistochemical analysis demonstrated that TrkC-positive ACC specimens also show high expression of Bcl2, a Trk target regulated via Erk 1/2, in agreement with activation of the TrkC pathway in real tumors. In normal salivary gland tissue, both TrkC and Bcl2 were expressed in myoepithelial cells, suggesting a principal role for this cell lineage in the ACC origin and progression. Sub-micromolar concentrations of a novel potent Trk inhibitor AZD7451 completely blocked TrkC activation and associated tumorigenic behaviors. Pre-clinical studies on ACC tumors engrafted in mice showed efficacy and low toxicity of AZD7451, validating our in vitro data and stimulating more research into its clinical application. In summary, we describe in ACC a previously unrecognized pro-survival neurotrophin signaling pathway and link it with cancer progression.

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Section: Introductionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

et al. 2012

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“…Interestingly, high TrkC expression was recently observed in comparison with normal breast tissue in about 84% of the infiltrating ductal carcinomas analyzed. 40 Additionally, through in vitro and in vivo experimental studies, the authors demonstrated that overexpression of FL wild-type TrkC is sufficient to promote proliferation and colony formation, as well as tumor growth in mouse models of breast cancer. Mechanistically, they attributed the oncogenic activity of TrkC to its ability to activate MAPK and PI3K pathways.…”

Section: Ink4amentioning

confidence: 99%

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

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REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway. Cell Death and Differentiation (2015) 22, 1353-1362 doi:10.1038/cdd.2014; published online 23 January 2015The transcription factor REST was originally discovered as a repressor of neuronal differentiation genes in non-neuronal lineages. Therefore, REST is considered as a master regulator of neurogenesis in development and maintenance of gene silencing. [1][2][3][4] Recently, it has been recognized that aberrant REST function also has a role in human malignancies, largely depending on the cellular context. 5 Focal genomic deletions targeting the REST locus have been found in colon adenocarcinoma and REST protein expression is often lost in small cell lung carcinoma cells. 6,7 In breast cancer, the loss of full-length (FL) REST protein is associated with disease recurrence and poor prognosis.8 However, the underlying mechanism of how REST protects against transformation in epithelial tissues has remained largely elusive.We have previously implicated the testis-specific protein, Y-encoded-like (TSPY-L) family of genes in cancer by identifying TSPYL5 expression as a prognostic marker of poor clinical outcome in breast cancer.9 TSPYL5 can interfere with p53-dependent cell-cycle arrest and oncogene-induced senescence triggering p53 ubiquitination and protein degradation.9 Besides TSPYL5, the TSPYL family of genes includes several other members (four coding genes and one pseudogene) whose functions are still unknown. All five proteins (TSPYL1, TSPYL2, TSPYL4, TSPYL5, and TSPYL6) are characterized by a predicted nucleosome assembly protein (NAP) domain, although functional evidence of NAP activity has not been reported of any of the TSPYL family members. TSPYL2, which shares only partial homology with TSPYL5, has been proposed as a candidate tumor suppressor in carcinoma cells.10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor comple...

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“…31,32 Xenograft assay Six-week-old female athymic nude mice used for the in vivo experiments were maintained in accordance with the standards of the Institutional Animal Care and Use Committee. A total of 2.5 Â 10 6 cells were injected into subcutaneous area of mice with matrigel (BD sciences, San Jose, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

et al. 2012

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Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-b (TGF-b) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-b target genes, PAI-I and CDK inhibitors such as p15 INK4b and p21 Cip1 . Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-b transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-b tumor suppressor activity.

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TrkC plays an essential role in breast tumor growth and metastasis

Cited by 68 publications

References 43 publications

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

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