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- W1436710786 abstract "Proc Amer Assoc Cancer Res, Volume 46, 20052271 Anti-HER2 antibody trastuzumab (Herceptin) has been used effectively to treat breast cancers that overexpress HER2. We and others have demonstrated that anti-HER2 antibodies suppress cancer growth primarily through induction of a cell cycle G1 arrest. We have also demonstrated that p27Kip1 upregulation is one of the key events that cause G1 arrest upon trastuzumab treatment. We have now shown that specific inhibition of CDK2 is another important event that contributes to induction of G1 arrest in SKBr3 and BT474 breast cancer cells that overexpress HER2. We have more precisely localized the position in the cell cycle where growth arrest occurs. Trastuzumab was able to dramatically inhibit the kinase activity and expression of CDK2, whereas the kinase activity and expression of CDK4 were not affected significantly by trastuzumab. Unlike p27Kip1 upregulation that occurs primarily through post-translational mechanism, CDK2 was downregulated at a transcriptional level indicated by Northern blotting and RT-PCR analysis. Moreover, trastuzumab effectively inhibited the promotor activity of CDK2. Trastuzumab decreased the kinase activity of cyclin E (because of CDK2 inhibition) although it had little effect on cyclin E expression. Overexpression of wild-type cyclin E or its more active lower molecular weight forms did not influence the response to trastuzumab. Cyclin D1 Expression was only affected by trastuzumab at late stages (after 24 hrs). Thus, trastuzumab preferentially targeted the CDK2-cyclin E complex during G1 phase. As a result, CDK2-cyclin E-induced Rb phosphorylation was more substantially inhibited by trastuzumab than CDK4-cylcin D-induced Rb phosphorylation. A marked reduction of CDK2-cyclin E activity and a modest reduction CDK4-cyclin D activity were associated with hypophosphorylated Rb protein so that more E2F1 was retained in Rb complex and that E2F1 activity was decreased. The differential effect of trastuzumab on CDK2 and CDK4 indicate trastuzmab-induced growth arrest occurs at late G1 phase of the cell cycle. This notion was further supported by examination of other cell cycle-dependent gene/protein expression. An early G1 marker c-Myc and a delayed-early marker ornithine decarboxylase were not significantly affected by trastuzumab treatment, whereas the late G1/S phase proteins DNA polymerase alpha and proliferating cell nuclear antigen were dramatically inhibited. These results suggest that growth arrest induced by anti-HER2 antibody blocks breast cancer cells in the late G1 phase of the cell cycle." @default.
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- W1436710786 date "2005-05-01" @default.
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- W1436710786 title "Growth arrest induced by anti-HER2 antibody blocks breast cancer cells in the late G1 phase of the cell cycle" @default.
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