Epithelial to mesenchymal transition in human breast epithelial cells transformed by 17beta-estradiol.
The estrogen dependence of breast cancer has long been recognized; however, the role of 17beta-estradiol (E(2)) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E(2) treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor beta1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation.
W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee, USA.
Yong
Y
Huang
Sandra V
SV
Fernandez
Shirlean
S
Goodwin
Patricia A
PA
Russo
Irma H
IH
Russo
Thomas R
TR
Sutter
Jose
J
Russo
D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002869:Chromosome Aberrations; D004848:Epithelium / Q000473:pathology*; D004958:Estradiol / Q000009:adverse effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019656:Loss of Heterozygosity; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D004958:Estradiol