A "NOTCH" Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer - PubMed (original) (raw)
Review
A "NOTCH" Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer
Rohan Kar et al. Genes (Basel). 2019.
Abstract
Notch signaling is a primitive signaling pathway having various roles in the normal origin and development of each multicellular organisms. Therefore, any aberration in the pathway will inevitably lead to deadly outcomes such as cancer. It has now been more than two decades since Notch was acknowledged as an oncogene in mouse mammary tumor virus-infected mice. Since that discovery, activated Notch signaling and consequent up-regulation of tumor-promoting Notch target genes have been observed in human breast cancer. Moreover, consistent over-expression of Notch ligands and receptors has been shown to correlate with poor prognosis in human breast cancer. Notch regulates a number of key processes during breast carcinogenesis, of which, one key phenomenon is epithelial-mesenchymal transition (EMT). EMT is a key process for large-scale cell movement during morphogenesis at the time of embryonic development. Cancer cells aided by transcription factors usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis. In this review, we recapitulate recent progress in breast cancer research that has provided new perceptions into the molecular mechanisms behind Notch-mediated EMT regulation during breast tumorigenesis.
Keywords: EMT; Notch; PI3K/Akt; breast cancer; cytokine; hypoxia; invasion; metastasis; signaling pathway.
Conflict of interest statement
The authors declare that they have no conflicts of interest.
Figures
Figure 1
(a) Notch receptor architecture: The N-terminal of the Notch receptor contains EGF repeats (approximately 29–36) followed by a Lin-12 Notch repeats (LNR) region. LNR is followed by the heterodimerized region (HD-N and HD-C) that, along with the LNR, forms the negative regulatory region (NRR). The HD region is also the site for the first cleavage (S1) that separates the HD-N and HD-C components. Together, the EGF repeats and NRR form the Notch extracellular domain (NECD). NECD is followed by the transmembrane region (TM), which is the site for the second (S2) cleavage mediated by matrix metalloproteinases (MMPs) (ADAM10/ADAM17). The TM region is followed by the most crucial part of the receptor—Notch intracellular domain (NICD). This region is made up of the nuclear localization sequence (NLS), RBPJ-associated molecule (RAM) domain, six to seven ankyrin (ANK) repeats, transcription activation domain (TAD) and PEST (Pro–Glu–Ser–Thr) domain. S3 is the site for γ-secretase-mediated cleavage that generates the NICD for nuclear transport. (b) Extracellular domain organization of Notch ligands Serrate and Delta: The N-terminal domain (NTD) is followed by the Delta–Serrate–LAG-2 (DSL) protein domain and Delta and OSM-11 DOS domain. DOS domains are not present in Dll-3 and Dll-4. Following DOS (Delta and OSM-11-like proteins), domains have varying numbers of EGF repeats. The Serrate ligands additionally have a cysteine-rich domain (CRD) that distinguishes serrate ligands from their Delta counterparts.
Figure 2
(a) The gamma secretase (γ-secretase) complex: It is comprised of presenilin enhancer (PEN-2), anterior pharynx-defective 1 (APH1) and nicastrin. Presenilins (PS1/PS2) are the catalytic components. (b) The five step canonical Notch pathway: (1) ADAM 10/17-mediated cleavage frees the Notch extracellular domain (NECD); (2) the receptor-NECD complex is endocytosed by epsin-mediated endocytosis; this initiates the Notch cascade; (3) γ-secretase mediated cleavage releases the transcriptionally active nuclear bound Notch intracellular domain (NICD); (4) NICD enters into the nucleus; and finally (5), NICD forms a complex with the DNA binding protein RBPj and a member of the mastermind-like (MAML) family of transcriptional co-activators to facilitate the transcription of Notch target genes. (c) Numerous genes are regulated by the Notch pathway that could play a role in epithelial–mesenchymal transitions (EMTs). CSL, CBF1, Suppressor of Hairless, Lag-1 transcription factor.
Figure 3
Notch-mediated epithelial–mesenchymal transition (EMT) cross-talk during breast carcinogenesis: The EMT process primarily involves the loss of epithelial markers and gain of mesenchymal markers. Once the cells acquire a mesenchymal phenotype, they first intravasate and later extravasate from the blood vessel to establish a distant metastasis. Post-extravasation, there occurs a reverse process called MET (mesenchymal–epithelial transition) that allows the mesenchymal cells to once again revert back to the epithelial type. The above diagram represents the probable cross-talk between three modules that could drive EMT during breast carcinogenesis; viz., the Notch/Cytokine module, the Notch/Akt module and the Notch/Hypoxia module. Inositol blocks both the activity of Notch and Akt and could serve as a potent therapeutic agent targeting EMT. It must be noted that Notch-mediated EMT via Akt and STAT-3 is mediated primarily by NF-κβ. NF-κβ, nuclear factor-kappa β; PP2A, protein phosphatase-2A; IL, interleukin; COX-2, cyclooxygenase-2; BC, breast cancer; VEGF, vascular endothelial growth factor.
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