title: Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors.
abstract: To address the role of transforming growth factor (TGF) beta in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-beta on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-beta1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-beta1 for as little as 2 weeks increased lung metastases >10-fold without a detectable effect on primary tumor cell proliferation or tumor size. DOX-induced active TGF-beta1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-beta and increased metastases. Antisense-mediated inhibition of TGF-beta1 in polyomavirus middle T antigen-expressing tumor cells also reduced basal cell motility, survival, anchorage-independent growth, tumorigenicity, and metastases. Therefore, induction and/or activation of TGF-beta in hosts with established TGF-beta-responsive cancers can rapidly accelerate metastatic progression.
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Muraoka-Cook
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kurokawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: James T
authors.initials: JT
authors.lastname: Forbes
authors.forename: L Renee
authors.initials: LR
authors.lastname: Roebuck
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.forename: Susan E
authors.initials: SE
authors.lastname: Moody
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009857:Oncogenes; D051785:Smad Proteins; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D051785:Smad Proteins; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1