title: An autocrine loop between TGF-β1 and the transcription factor brachyury controls the transition of human carcinoma cells into a mesenchymal phenotype.
abstract: The epithelial-mesenchymal transition (EMT) is a process associated with the metastasis of solid tumors as well as with the acquisition of resistance to standard anticancer modalities. A major initiator of EMT in carcinoma cells is TGF-β, which has been shown to induce the expression of several transcription factors ultimately responsible for initiating and maintaining the EMT program. We have previously identified Brachyury, a T-box transcription factor, as an inducer of mesenchymal features in human carcinoma cells. In this study, a potential link between Brachyury and TGF-β signaling has been investigated. The results show for the first time that Brachyury expression is enhanced during TGF-β1-induced EMT in various human cancer cell lines, and that a positive feedback loop is established between Brachyury and TGF-β1 in mesenchymal-like tumor cells. In this context, Brachyury overexpression is shown to promote upregulation of TGF-β1 at the mRNA and protein levels, an effect mediated by activation of the TGF-β1 promoter in the presence of high levels of Brachyury. Furthermore, inhibition of TGF-β1 signaling by a small-molecule inhibitor of TGF-β receptor type I decreases Brachyury expression, induces a mesenchymal-to-epithelial transition, and renders cancer cells more susceptible to chemotherapy. This study thus has implications for the future development of clinical trials using TGF-β inhibitors in combination with other anticancer agents.
authors.affiliation: Corresponding Author: Claudia Palena, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH; 10 Center Drive, Room 8B14, MSC 1750, Bethesda, MD 20892. palenac@mail.nih.gov.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Larocca
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Cohen
authors.forename: Romaine I
authors.initials: RI
authors.lastname: Fernando
authors.forename: Bruce
authors.initials: B
authors.lastname: Huang
authors.forename: Duane H
authors.initials: DH
authors.lastname: Hamilton
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D025461:Feedback, Physiological; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine; D000098908:Brachyury Protein
chemical_list: D002945:Cisplatin; D005326:Fetal Proteins; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; D020825:T-Box Domain Proteins; D053773:Transforming Growth Factor beta1; D014747:Vinblastine; D000077235:Vinorelbine; D000098908:Brachyury Protein; C511004:SD-208