Breast cancer (BC) has been widely studied as the result of tempo-spatial aberrations occurring during normal breast tissue development. Similarities between mammary embryonic development and cell-transformation suggest that the underlying mechanisms behind mammary gland development are mostly the ones that are disturbed during various stages of mammary tumorigenesis. Nevertheless, based on the expression of immunohistochemistry (IHC) markers, such as estragon receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), BC cancer can be split into four major subtypes; namely, ER+/PR+/HER2−, ER+/PR+/HER2+, ER-/PR-/HER2+ and ER-/PR-/HER2−. Further, based upon the usage of “intrinsic” genes, BC can be split into another four groups; namely, luminal A, luminal B, HER2 positive and basal-like. Interestingly, each of the aforementioned IHC-defined subtypes relate to a basic gene expression profiling (GEP)-defined subgroup. For instance, luminal A and luminal B roughly correspond to ER+/PR+/HER2− and ER+/PR+/HER2+ statuses, respectively; albeit a small percentage of ER+/PR+/HER2− tumors (with Ki67 expression) are classified as luminal B type. The subtype with ER−/PR−/HER2− status (also called triple negative breast cancer or TNBC) is primarily comprised of metaplastic, basal-like breast tumors that are rich in interferons and express low levels of claudin]. BC cells acquire metastatic abilities that allow them to relocate to sites far away from the primary loci. And often, this metastatic potential determines tumor grade and drives prognosis in patients.
Epithelial-mesenchymal “transformation” was first studied by Elizabeth Hay using a model of chick primitive streak formation. Later on, researchers described the process as a morphological conversion happening at specific sites in embryonic epithelia to give rise to distinct migratory cells. Consequently, the term “transformation” was replaced with “transition” and the phenomenon came known as epithelial–mesenchymal transition (EMT). BC cells, alike many other cancer cells, utilize EMT that allows the epithelial cells to shed their markers and acquire mesenchymal features.Therefore, EMT can also be defined as the trans-differentiation of static epithelial cells into motile mesenchymal cells. EMT is a reversible process (mesenchymal–epithelial transition (MET) being the opposite of EMT) during which epithelial cells acquire mesenchymal properties and exhibit reduced intercellular adhesion and increased motility. The epithelial cells break through the basal membrane and traverse to distant sites by triggering subtle changes in their cytoskeleton architecture. EMT is an important aspect of mammalian growth and development and is constantly involved in processes such as wound healing, stem cell bearings, tumorigenesis, etc.
EMT can been classified into three major types: Type 1 EMT that normally operates during embryonic development; Type 2 EMT that is associated with wound healing, tissue regeneration and organ fibrosis; and Type 3 EMT that takes precedence in epithelial cancer cells and participates in metastasis and cancer progression.EMT is driven by a panel of transcription factors that are known to play acute roles during embryogenesis, and also during de-differentiation of cancer cells. They trigger EMT through the transcriptional control of E-cadherin and include members such as Snail-1/2, ZEB-1/2, Twist-1/2, FOXC-1/2, TCF-3 and GSC. Most importantly, Snail and Twist are capable alone, if activated, to prompt a mesenchymal/cancer stem cell-like (CSC) phenotype in human immortalized human mammary epithelial cells. Besides, Twist-1, FOXC-2, Snail-1, ZEB-2 and Twist-2 are reportedly over-expressed in stem-like cells isolated from primary breast carcinomas, in contrast with more differentiated cancer cells.Metastatic breast cancer is largely incurable; therefore, proper understanding of EMT regulation of the metastatic cascade can possibly lead to the development of novel targeted therapeutic strategies.
The Notch signaling pathway plays an important role during normal breast development and during breast cancer development and progression. Different subtypes of mammalian Notch are sensitive to delicate changes in protein levels, and a number of studies have established a key relationship between breast carcinogenesis and Notch deregulation. However, a lot remains to be deciphered especially in the context of breast cancer. Most importantly, Notch cooperates with a panel of signaling pathways, transcription factors, RNAs and a multitude of modulators (activators/inhibitors), thereby making the interactions hard to comprehend]. For instance, Notch receptors (Notch-1/2/3/4) interact with the epidermal growth factor receptor tyrosine kinase family (RTK) of proteins, such as HER-1, 2, 3 and 4. Over-expressions of HER and/or Notch activity have been reported in BC, thereby identifying Notch as a potent oncogene capable of advancing malignant state in Bc.Moreover, Notch maintains HER-induced downstream signals radiated to pathways such as mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). Altogether, these equip the BCs to resist molecular targeted therapies, undergo the process of EMT, and facilitate cellular invasion and metastasis. This review focuses on the EMT program and identifies key Notch-based interactions that could possibly have an important role in driving EMT during BC tumorigenesis. Additionally, the review highlights Notch based interactions in several other cancers, which may act as drivers of the EMT program..
Shuaib Burgee is a Biotechnologist at Sharda University and can be mailed at shuaibburgee741@gmail.com
