title: Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations.
abstract: Approximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT-RII) in the type II transforming growth factor beta (TGF-beta) receptor (TGFBR2), a required component of the TGF-beta receptor. The BAT-RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF-beta. In cultured epithelial cells, TGF-beta can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. These effects are context- and tissue type-dependent, raising questions about which of these in vitro effects of TGF-beta signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII. Colon cancers with mutant BAT-RII were found to have increased proliferation compared to cancers with wild-type BAT-RII. Assessment of cdk4, cyclin D1 and p27(kip1) expression revealed that only cdk4 expression was increased in the cancers with mutant BAT-RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. wgrady@fhcrc.org
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.forename: Patty
authors.initials: P
authors.lastname: Trobridge
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.forename: Nina
authors.initials: N
authors.lastname: Munoz
authors.forename: Joseph
authors.initials: J
authors.lastname: Olechnowicz
authors.forename: Kelly
authors.initials: K
authors.lastname: Ferguson
authors.forename: Shiva
authors.initials: S
authors.lastname: Gautam
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012189:Retrospective Studies; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4; D000077294:Receptor, Transforming Growth Factor-beta Type II