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

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.

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

“…Using this model, we then characterized gene expression patterns involved with EMT transduction in both a cancerous and noncancerous cell line from two different tissue sites and define a shared EMT‐associated GES from which we then independently validated the top differentially expressed genes by RT‐qPCR. The strong overlap between the 58 genes identified from our EMT GES with a published core EMT GES suggest that these 58 genes may be part of a larger core set of EMT‐genes that are neither tissue or cell type specific 8. Further studies will be required to confirm this, but these results are nonetheless intriguing.…”

“…The top‐10 upregulated common genes are SERPINB3, SERPINB4, SCG5, FAP, MMP9, GPR68, SERPINE1,CXCR7, ADAM19 , and SLAMF8 ; the top‐10 downregulated common genes are KRT15 PSCA, FGFBP1, FXYD3, MAL2, GPR110, C10orf116, S100P, SUSD2 , and MYO5C . After comparing our 571‐EMT‐GES with a previously published 246‐gene EMT‐core‐GES in breast cancer cells, we found 58 overlapping genes (=5 × 10 −42 , hypergeometric distribution) (Table S3), suggesting that these genes are a part of a core set of EMT‐genes that are neither tissue or cell type specific 8.…”

“…While loss of E‐cadherin expression represents a primal event in EMT, we increasingly appreciate that EMT is a complex process that is orchestrated by activation and repression of a growing and still incomplete list of genes, proteins, and transcriptional factors including ZEB1, SNAIL, TWIST, CDH2, and VIM among others 5, 6, 7. Although several different EMT‐related gene expression signatures (GES) have been reported to date attempting to capture key EMT‐associated genes and regulators of EMT, they have been limited in part by variations observed between cell lines, limited concordance between different EMT induction models, and lack of functional validation 8, 9, 10, 11, 12. Therefore, additional studies are still needed to identify both a robust, common set of EMT‐associated genes and regulators in order to help improve our understanding of EMT, which could serve to drive future prognostic approaches and individualized therapies.…”

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

“…Claudin-2 and breast cancer liver metastasis S Tabariès et al by features of an epithelial-to-mesenchymal transition, enhanced stem cell characteristics and resistance to chemotherapy (Creighton et al, 2009(Creighton et al, , 2010Hennessy et al, 2009;Prat et al, 2010;Taube et al, 2010). At the present time, the status of claudin-2 expression within these 'claudin-low' tumors has not been described.…”

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

“…Mutations in the human FOXC1 gene underlie Axenfeld-Rieger syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma. In breast cancer, FOXC1 expression is strongly associated with the basal-like subtype of breast cancer and postulated to be a marker of poor prognosis (Ray et al, 2010;Taube et al, 2010). FOXC1 expression in breast cancers appears to be controlled at the transcriptional level, and methylation of the FOXC1 promoter was shown to be an independent prognostic marker associated with survival (Dejeux et al, 2010) and CD44-positive (basal-like) breast tumors.…”