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Shc Dominant Negative Disrupts Cell Cycle Progression in Both G₀-G₁ and G₂-M of ErbB2-positive Breast Cancer Cells¹

Departments of Pathology and Laboratory Medicine and Medicine, Brown University, and Roger Williams Medical Center [L. E. S., A. R. F.], Providence, Rhode Island 02908, and Beirne Carter Center for Immunology Research and Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908 [K. S. R.].

The Shc protein helps to transmit signals from receptor and cytoplasmic tyrosine kinases to Ras. We have shown that several breast cancer cell lines (MDA-MB-453, BT-474, MDA-MB-361, and SKBR3), which overexpress the ErbB2 receptor tyrosine kinase, contain constitutively tyrosine phosphorylated Shc. To investigate the role of Shc in these cells, we transfected them with a Shc-Y317F dominant-negative mutant defective in signaling to Ras. The transfectants were unable to form stable colonies, suggesting a critical role for Shc in the proliferation of these cells. In contrast, dominant-negative Shc transfectants of the nontransformed breast epithelial cell line HBL-100 grew normally. Surprisingly, cell cycle analysis of transfected SKBR3 cells suggested that the cells were blocked not only in G₀-G₁, but also in G₂-M. The G₂-M block was unexpected because Shc-Y317 is downstream of receptor tyrosine kinases that drive the early events in the cell cycle. Both the G₀-G₁ and G₂-M arrest were rescued by transfection with wild-type Shc or oncogenic Ras 12V. Rescue by Ras suggests that Shc Y317 signals upstream of Ras, and that Shc to Ras effector pathways are involved in G₂-M, although confirmation awaits a detailed molecular analysis. Most importantly, this work provides the first evidence for Shc involvement in G₂-M.

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