Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes.
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-beta1. 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-beta1, and FOXC2 being commonly induced. Up-regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF-beta1 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-beta1 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.
Taube
Joseph H
JH
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
Herschkowitz
Jason I
JI
Komurov
Kakajan
K
Zhou
Alicia Y
AY
Gupta
Supriya
S
Yang
Jing
J
Hartwell
Kimberly
K
Onder
Tamer T
TT
Gupta
Piyush B
PB
Evans
Kurt W
KW
Hollier
Brett G
BG
Ram
Prahlad T
PT
Lander
Eric S
ES
Rosen
Jeffrey M
JM
Weinberg
Robert A
RA
Mani
Sendurai A
SA
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D057167:Claudins / Q000235:genetics*; D016000:Cluster Analysis; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D051956:Goosecoid Protein / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics
D057167:Claudins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C497992:GSC protein, human; D051956:Goosecoid Protein; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051879:Twist-Related Protein 1