Abstract
Simple SummaryEpithelial–mesenchymal transition (EMT) and its reverse process mesenchymal–epithelial transition (MET) are considered critical events in the cancer progression. These programs are tightly connected with the development of metastasis–the lethal stage of the disease. Both EMT and MET shape the biology of unusually aggressive and heterogeneous triple-negative breast cancer (TNBC). In this review, we summarize the current knowledge of EMT/MET plasticity in the context of TNBC, with a special focus on drivers and mechanisms behind these processes.Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.
Highlights
One of the key mechanisms that contributes to phenotypic plasticity and heterogeneity is the epithelial–mesenchymal transition (EMT) and its reverse program known as mesenchymal–epithelial transition (MET)
Cancer cells comprising the triple-negative breast tumors are often enriched in mesenchymal traits when compared to other breast cancer subtypes, suggesting the presence of high degree of plasticity in Triple-negative breast cancer (TNBC)
The EMT and MET programs, aberrantly activated by tumor cells and employed at different stages of cancer progression enable these cancer cells to dynamically change their phenotype, a feature that might be critical for successful metastatic dissemination and overcoming the multiple obstacles on route to a final destination-distant site parenchyma
Summary
One of the key mechanisms that contributes to phenotypic plasticity and heterogeneity is the epithelial–mesenchymal transition (EMT) and its reverse program known as mesenchymal–epithelial transition (MET) Both of these fundamental programs play specific roles in embryonic development and adult tissue homeostasis. E/M states, co-expressing both epithelial and mesenchymal markers and partially bearing features of both phenotypes Some of these highly plastic and aggressive hybrid phenotypic states provide cancer cells with increased fitness and flexibility required for tumor development. Metastatic TNBC demonstrate enrichment of driver and targetable CNA relative to primary tumors [51] and majority of patients exhibit complex aneuploid rearrangements [52,53,54] These studies provide mostly descriptive data of TNBC cellular and genomic heterogeneity, and further mechanistic studies are needed to functionally link particular populations with EMP
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