Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human t umours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intra cellularly expressed, ER-targeted single-chain antibody (scFV-5R), Inducibl e expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cel l line leads to loss of plasma membrane localized ErbB2, Simultaneously, th e activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggest ing that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to ac cumulate in the G1 phase of the cell cycle, This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27(Kip1) from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27(Kip1) sequestration, decreased in the a bsence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We p ropose that c-Myc is a primary effector of ErbB2-mediated oncogenicity and functions to prevent normal p27(Kip1) control of cyclinE/CDR2.