Role of Notch and its oncogenic signaling crosstalk in breast cancer - PubMed (original) (raw)

Review

Role of Notch and its oncogenic signaling crosstalk in breast cancer

Shanchun Guo et al. Biochim Biophys Acta. 2011 Apr.

Abstract

The Notch signaling plays a key role in cell differentiation, survival, and proliferation through diverse mechanisms. Notch signaling is also involved in vasculogenesis and angiogenesis. Moreover, Notch expression is regulated by hypoxia and inflammatory cytokines (IL-1, IL-6 and leptin). Entangled crosstalk between Notch and other developmental signaling (Hedgehog and Wnt), and signaling triggered by growth factors, estrogens and oncogenic kinases, could impact on Notch targeted genes. Thus, alterations of the Notch signaling can lead to a variety of disorders, including human malignancies. Notch signaling is activated by ligand binding, followed by ADAM/tumor necrosis factor-α-converting enzyme (TACE) metalloprotease and γ-secretase cleavages that produce the Notch intracellular domain (NICD). Translocation of NICD into the nucleus induces the transcriptional activation of Notch target genes. The relationships between Notch deregulated signaling, cancer stem cells and the carcinogenesis process reinforced by Notch crosstalk with many oncogenic signaling pathways suggest that Notch signaling may be a critical drug target for breast and other cancers. Since current status of knowledge in this field changes quickly, our insight should be continuously revised. In this review, we will focus on recent advancements in identification of aberrant Notch signaling in breast cancer and the possible underlying mechanisms, including potential role of Notch in breast cancer stem cells, tumor angiogenesis, as well as its crosstalk with other oncogenic signaling pathways in breast cancer. We will also discuss the prognostic value of Notch proteins and therapeutic potential of targeting Notch signaling for cancer treatment.

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Figures

Fig. 1

Notch signaling and its possible downstream targets in breast cancer. Mammalian ligands of Notch are membrane-bound proteins containing an extracellular NH2-terminal Delta/Serrate/LAG2 (DSL) motif followed by epidermal growth factor (EGF)-like repeats. Notch receptors are broadly expressed on the cell surface as heterodimers containing a Notch extracellular domain (NECD) composed by multiple extracellular EGF-like repeats, three Lin12/Notch repeats (LNR or NRR) and a heterodimerization (HD) domain followed by a transmembrane subunit (N™). Notch receptor cytoplasmatic region or Notch intracellular domain (NICD) contains one nuclear localization signals (NLS) linking RAM domain to six ankyrin (ANK) repeats (ANK domain) followed by an additional bipartite NLS, a loosely defined transactivation domain (TAD), and a conserved proline/glutamic acid/ser/threo-rich domain (PEST domain). In the absence of activated Notch signaling, the DNA binding protein RBP-Jk (CSL/CBF1/Su (H)/Lag1, a transcription factor) forms a complex with corepressor molecules that represses transcription of target genes. Ligand binding to NECD triggers successive proteolytic cleavages of Notch cytoplasmatic region; S2: by TACE (ADAM) and S3/S4: by γ-secretase, proteases resulting in the release of NICD, which translocates into nucleus and removes corepressors from RBP-Jk. This allows RBP-Jk to recruit a coactivator complex composed of Mastermind (MAM) and several transcription factors to transcriptionally activate Notch target genes. Activation of Notch could impact on the following processes in breast cancer: 1) inhibition of apoptosis through upregulation of survivin [–52] and Bcl-2 protein family [294]; 2) activation of the cell cycle through upregulation of Cyclin D1 [73]; 3) promotion of cell proliferation/survival through upregulation of PI-3K/Akt [211], TGF-β [134], c-Myc [46], NF-κB [86], EGFR [117] and IL-6 [154] pathways; 4) stimulation of angiogenesis and VEGF/VEGFR-2 autocrine/paracrine loop by upregulation of IL-1 system and VEGF/VEGFR-2 ([140, 161] and unpublished results); 5) suppression of cancer growth in some cellular situations. For example, Notch2 signaling may function as a tumor suppressor through upregulation of PTEN or downregulation of PI-3K/Akt/mTOR [295]. Note: (*): TAD is not present in Notch3 and 4.

Fig. 2

Potential Notch signaling crosstalk with other pathways in breast cancer. OB-R: leptin receptor ; IL-1: pro-inflammatory/-angiogenic cytokine interleukin-1; NILCO: Notch-IL-1-Leptin crosstalk outcome; E2: 17β-estradiol; HER/ErbB: HER1/EGFR, HER2, HER3 and HER4, encode for RTK-transmembrane proteins; NF-κB: a transcription factor family, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-6: pro-inflammatory/-angiogenic cytokine, interleukin-6; STAT3: Signal transducer and activator of transcription 3; PDGF-D: Platelet-derived growth factor D; TGF-β: transforming growth factor β; miRNA: MicroRNA; PI-3K: phosphatidylinositol 3-kinase; mTOR: mammalian target of rapamycin; HIF-1: hypoxia-inducible transcription factor 1; VEGF: vascular endothelial growth factor; VEGFR-2: vascular endothelial growth factor receptor-2.

References

1. Jemal A, Center MM, Desantis C, Ward EM. Global Patterns of Cancer Incidence and Mortality Rates and Trends. Cancer Epidemiol Biomarkers Prev. 2010;19:1893–1907. - PubMed
1. Korkaya H, Wicha MS. HER-2, notch, and breast cancer stem cells: targeting an axis of evil. Clin Cancer Res. 2009;15:1845–1847. - PubMed
1. Wang Z, Li Y, Ahmad A, Azmi AS, Banerjee S, Kong D, Sarkar FH. Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim Biophys Acta. 2010 [Epub ahead of print] - PMC - PubMed
1. Farnie G, Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev. 2007;3:169–175. - PubMed
1. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol. 2004;14:341–347. - PubMed

Role of Notch and its oncogenic signaling crosstalk in breast cancer - PubMed (original) (raw)