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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 35; pp. 15449 - 15454
• Main Authors: Taube, Joseph H., Herschkowitz, Jason I., Komurov, Kakajan, Zhou, Alicia Y., Gupta, Supriya, Yang, Jing, Hartwell, Kimberly, Onder, Tamer T., Gupta, Piyush B., Evans, Kurt W., Hollier, Brett G., Ram, Prahlad T., Lander, Eric S., Rosen, Jeffrey M., Weinberg, Robert A., Mani, Sendurai A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31.08.2010; National Acad Sciences
• Subjects: Biological Sciences; Breast cancer; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cadherins; Cancer; Cell Line; Cell Line, Tumor; Cell lines; Cell migration; Cellular biology; Claudins - genetics; Cluster Analysis; Down-Regulation; E- double prime Cadherin; Epithelial cells; Epithelial Cells - metabolism; epithelium; Female; Forkhead Transcription Factors - genetics; Gene expression; Gene Expression Profiling; gene expression regulation; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Goosecoid Protein - genetics; Humans; Invasiveness; Mesenchymal stem cells; Mesoderm - metabolism; Metastases; Metastasis; migratory behavior; neoplasm cells; Oligonucleotide Array Sequence Analysis; Oncology; patients; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Signatures; Snail Family Transcription Factors; Stem cells; Transcription factors; Transcription Factors - genetics; Transforming Growth Factor beta1 - genetics; Transforming growth factor- beta 1; Tumors; Twist-Related Protein 1 - genetics
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1004900107

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.