Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer

Cohen, Brenda; Shimizu, Mamiko; Izrailit, Julia; Ng, Nancy; Buchman, Yuri; Pan, James; Dering, Judy; Reedijk, Michael

doi:10.1007/s10549-009-0621-9

Cited by 145 publications

(130 citation statements)

References 50 publications

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“…Consistent with this, activated Notch signaling (2-4) and up-regulation of growth-promoting Notch target genes (5)(6)(7)(8)(9), are observed in breast cancer. Notch is a highly conserved intercellular signaling system present in multicellular organisms (10).…”

supporting

confidence: 64%

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer

Izrailit

Berman

Datti

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

111

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Expression of the Notch ligand Jagged 1 (JAG1) and Notch activation promote poor-prognosis in breast cancer. We used high throughput screens to identify elements responsible for Notch activation in this context. Chemical kinase inhibitor and kinase-specific small interfering RNA libraries were screened in a breast cancer cell line engineered to report Notch. Pathway analyses revealed MAPK-ERK signaling to be the predominant JAG1/Notch regulator and this was supported by gene set enrichment analyses in 51 breast cancer cell lines. In accordance with the chemical screen, kinome small interfering RNA high throughput screens identified Tribbles homolog 3 (TRB3), a known regulator of MAPK-ERK, among the most significant hits. We demonstrate that TRB3 is a master regulator of Notch through the MAPK-ERK and TGFβ pathways. Complementary in vitro and in vivo studies underscore the importance of TRB3 for tumor growth. These data demonstrate a dominant role for TRB3 and MAPK-ERK/TGFβ pathways as Notch regulators in breast cancer, establishing TRB3 as a potential therapeutic target.

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supporting

confidence: 64%

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer

Izrailit

Berman

Datti

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

111

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“…34,35 In our experimental model, however, the 2 probe sets for CCND1 did not pass our threshold for differential expression (fold change of 0.679 for 208711_s_at and 0.022 for 208712_at), suggesting that CCND1 is not regulated by NOTCH in MCL. This finding is in keeping with an overriding effect of the translocation t(11;14) on transcriptional regulation of CCND1.…”

Section: Notch1 Mutations In MCL 1967mentioning

confidence: 72%

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Kridel

Meissner

Rogić

et al. 2012

Blood

304

254

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Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P ‫؍‬ .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

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“…Notch target gene expression (36,37) can provide a surrogate for activity, but Notch target gene profiles vary between cell types and context. Thus, we have focused on the presence of g-secretase-cleaved NICD Ã .…”

Section: Discussionmentioning

confidence: 99%

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Choy¹,

Hagenbeek²,

Solon³

et al. 2017

Cancer Research

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Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4. This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers.

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Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer

Cited by 145 publications

References 50 publications

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

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