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Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations
Author(s) -
Grady William M.,
Willis Joseph E.,
Trobridge Patty,
RomeroGallo Judith,
Munoz Nina,
Olechnowicz Joseph,
Ferguson Kelly,
Gautam Shiva,
Markowitz Sanford D.
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21399
Subject(s) - microsatellite instability , biology , cancer research , cyclin dependent kinase , colorectal cancer , kinase , cyclin d1 , cell growth , cell cycle , cancer , microbiology and biotechnology , genetics , gene , microsatellite , allele
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 β (TGF‐β) receptor ( TGFBR2 ), a required component of the TGF‐β receptor. The BAT‐RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF‐β. In cultured epithelial cells, TGF‐β 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‐β 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. © 2005 Wiley‐Liss, Inc.