Epithelial-Mesenchymal Transition in Breast Cancer Relates to the Basal-like Phenotype

TLDR

Epithelial‑mesenchymal transition (EMT) is the loss of epithelial traits and gain of mesenchymal characteristics, and in carcinomas it is linked to increased aggressiveness, invasion, and metastasis. The study aimed to determine the prevalence of EMT in breast cancers and to test whether basal‑like cells possess intrinsic plasticity for mesenchymal transition. Researchers performed a tissue‑microarray immunohistochemical analysis of 479 invasive breast carcinomas and 12 carcinosarcomas using 28 markers, and conducted low‑density in vitro experiments on MCF10A cells to induce EMT‑like changes. Clustering showed that up‑regulation of EMT and extracellular‑matrix markers, together with loss of epithelial markers, preferentially occurs in basal‑like tumors, and that low‑density MCF10A cells undergo spontaneous EMT‑like changes and genetic program alterations, suggesting that EMT in breast tumors is confined to a basal genetic context and may drive their aggressiveness and metastatic spread.

Abstract

Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the "basal-like phenotype." Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.