Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes

TLDR

The epithelial‑to‑mesenchymal transition (EMT) generates invasive, migratory, stem‑like cancer cells, and is driven by transcription factors such as Goosecoid, Snail, Twist, and the secreted cytokine TGF‑β1, each of which can independently induce EMT in human mammary epithelial cells. The study aimed to elucidate the poorly understood interactions among these EMT regulators. By overexpressing each EMT inducer, the authors observed that they up‑regulate a subset of other EMT‑inducing transcription factors (including Twist, Zeb1, Zeb2, TGF‑β1, and FOXC2) and derived a core EMT signature from the shared gene‑expression changes, notably up‑regulation of Gsc, Snail, Twist, TGF‑β1 and down‑regulation of E‑cadherin. The findings revealed that Slug and FOXC2 induction by Snail or Twist is independent of TGF‑β1 signaling, that Twist and Snail gene‑expression signatures are most similar while Goosecoid is least similar, and that the EMT core signature is strongly associated with claudin‑low and metaplastic breast cancer subtypes, negatively correlates with pathological complete response, and that FOXC1 expression predicts poor patient survival.

Abstract

The epithelial-to-mesenchymal transition (EMT) produces cancer cells that are invasive, migratory, and exhibit stem cell characteristics, hallmarks of cells that have the potential to generate metastases. Inducers of the EMT include several transcription factors (TFs), such as Goosecoid, Snail, and Twist, as well as the secreted TGF-β1. Each of these factors is capable, on its own, of inducing an EMT in the human mammary epithelial (HMLE) cell line. However, the interactions between these regulators are poorly understood. Overexpression of each of the above EMT inducers up-regulates a subset of other EMT-inducing TFs, with Twist, Zeb1, Zeb2, TGF-β1, and FOXC2 being commonly induced. Up-regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF-β1 signaling. Gene expression signatures (GESs) derived by overexpressing EMT-inducing TFs reveal that the Twist GES and Snail GES are the most similar, although the Goosecoid GES is the least similar to the others. An EMT core signature was derived from the changes in gene expression shared by up-regulation of Gsc, Snail, Twist, and TGF-β1 and by down-regulation of E-cadherin, loss of which can also trigger an EMT in certain cell types. The EMT core signature associates closely with the claudin-low and metaplastic breast cancer subtypes and correlates negatively with pathological complete response. Additionally, the expression level of FOXC1, another EMT inducer, correlates strongly with poor survival of breast cancer patients.