The Notch Pathway Inhibits TGFβ Signaling in Breast Cancer through HEYL-Mediated Crosstalk

Han, Liang; Diehl, Adam; Nguyen, Nguyen K.; Korangath, Preethi; Teo, Wei Wen; Cho, Soonweng; Kominsky, Scott L.; Huso, David L.; Feigenbaum, Lionel; Rein, Alan; Argani, Pedram; Landberg, Göran; Gessler, Manfred; Sukumar, Saraswati

doi:10.1158/0008-5472.can-14-0816

Cited by 29 publications

(30 citation statements)

References 30 publications

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“…30,31,41 A most recent study found that repression of TGF-β signaling by Notch acting through Hes-related family bHLH transcription factor with YRPW motif-like might promote initiation of breast cancer. 32 In this case, Hes-related family bHLH transcription factor with YRPW motif-like represses TGF-β activity by binding to TGF-β-activated Smad proteins. Our finding describes a different mechanism by which Notch interacts with TGF-β in the context of pancreatic cancer initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

“…29 Interestingly, crosstalk between Notch and TGF-β signaling pathways has been documented in other tissues. [30][31][32] We therefore examined TGF-β ligand and receptor expression in the Lfng knockout pancreas by quantitative reverse transcription PCR. Interestingly, a significant decrease was seen in the levels of Tgfb1, Tgfb2 and Tgfbr2 mRNA in Lfng flox/flox ;Pdx1-Cre (LC) pancreata as compared with Lfng flox/flox (L) or Pdx1-Cre (C) controls (Figure 6a).…”

Section: Notch Activation Antagonizes Tgf-β Signaling In the Mouse Pamentioning

confidence: 99%

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Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer

2015

Oncogene

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Notch controls pancreatic differentiation during development and is reactivated in pancreatic cancer. In recent years, the importance of Notch signaling in pancreatic tumorigenesis has become increasingly evident; however, it remains unclear how Notch activities are regulated in this context. Here we report differential regulation of Notch receptors by Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats in the Notch extracellular domain, during pathogenesis of Kras-induced pancreatic ductal adenocarcinoma (PDAC). We show that Lfng is uniquely expressed in a subset of acinar cells in the adult pancreas. Deletion of Lfng in the Kras(LSL-G12D/+);Pdx1-Cre mouse model caused increased activation of Notch3 throughout PDAC initiation and progression, and Notch1 after the onset of disease, associated with marked upregulation of Notch target gene Hes1. Deletion of Lfng also resulted in accumulation of Aldh1-positive cell population. We found that loss of Lfng significantly accelerated Kras-initiated PDAC development and shortened survival of the PDAC mice. Interestingly, Lfng-deficient tumors showed a propensity for a poorly differentiated state with features of epithelial-to-mesenchymal transition. Likewise, knockdown of LFNG in human PDAC cell lines caused elevated Notch activation, associated with either accelerated cell proliferation or expanded Aldh1-positive cell population. Deletion of Lfng resulted in downregulation of Tgfb1, Tgfb2 and Tgfbr2 expression in the wild-type pancreas at all ages examined, and in the Kras(LSL-G12D/+);Pdx1-Cre pancreas after PDAC onset, as well as reduced phospho-Smad2 levels in pancreatic tumors. We provide evidence that Lfng regulates transforming growth factor (TGF)-β signaling through Notch-mediated transcriptional repression of TGF-β pathway genes. Taken together, our results reveal a potent tumor-suppressive function for Lfng and crosstalk between Notch and TGF-β pathways in the pancreas, which provides new insight into initiation of PDAC and signals involved in disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Notch Activation Antagonizes Tgf-β Signaling In the Mouse Pamentioning

confidence: 99%

Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer

2015

Oncogene

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“…HEYL is regarded as a Notch effector, and upregulated HEYL expression has been reported in ovarian, breast and colon cancer (32). Han et al (33) demonstrated that HEYL was associated with Smad protein expression, transforming growth factor β signaling, and initiating and progressing breast cancer. SFRP2 may augment Wnt16B signaling to promote a malignant phenotype and therapeutic resistance in the damaged tissue microenvironment, and increased SFRP2 expression has been reported to be associated with a poorer clinical outcome in colorectal cancer (34).…”

Section: Characteristics Of the Eight Csc-associated Genesmentioning

confidence: 99%

Cancer stem cell associated eight gene‑based signature predicts clinical outcomes of colorectal cancer

et al. 2018

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Previous studies have suggested that cancer stem cells serve crucial functions in tumorigenesis, metastasis and therapy failure. Stem cell signaling transduction pathways are frequently dysregulated in cancer and associated with tumorigenesis, metastasis and the cell cycle, which are necessary for cancer proliferation. However, cancer stem cell-associated gene signatures have not been established for predicting patient outcomes in colorectal cancer. Using a gene-mining approach, the present study performed mRNA expression profiling in large colorectal cancer cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, including a TCGA colorectal cancer cohort (n=383) and three independent validation series GSE39582 (n=582), GSE17536 (n=177) and GSE17537 (n=55). The present study identified that an eight-gene signature in cancer stem cell signaling was associated with the overall survival and disease/recurrence-free survival of patients with colorectal. On the basis of this signature, patients in the TCGA training sets were divided into high-risk and low-risk subgroups with a significantly different overall survival rate (hazard ratio, 2.38; P=0.0005). The prognostic value of this signature was confirmed using three independent GEO colorectal cancer sets. Identifying this prognostic stem cell signaling signature may provide an efficient classification tool for clinical prognosis evaluation, and facilitate cancer stem cell-targeted therapy.

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“…Hey2 overexpression increases hepatocellular carcinoma cell viability and proliferation (48). HeyL can promote breast cancer initiation through interaction with TGFb-activated Smad3 (31). Interestingly, HeyL promotes p53-induced cell-cycle arrest which results in suppression of cancer cell proliferation and induction of cancer cell apoptosis in hepatocellular carcinoma (49).…”

Section: The Roles Of Hey Proteins In Cancer Metastasismentioning

confidence: 99%

“…For example, Notch and TGFb have synergetic carcinogenic effects in lung carcinoma, head and neck squamous, esophageal adenocarcinoma, renal cell carcinoma, thyroid carcinoma, and breast cancer (31,(143)(144)(145)(146). Because both TGFb and Notch signaling can activate Hey, the simultaneous inhibition of both pathways might result in better outcomes than blockade of either individually.…”

Section: Combination Of Therapiesmentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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The Notch Pathway Inhibits TGFβ Signaling in Breast Cancer through HEYL-Mediated Crosstalk

Cited by 29 publications

References 30 publications

Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer

Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer

Cancer stem cell associated eight gene‑based signature predicts clinical outcomes of colorectal cancer

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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