a context-specific role for retinoblastoma protein-dependent negative growth control in suppressing mammary tumorigenesis视网膜母细胞瘤protein-dependent负增长控制特定于上下文的作用抑制乳腺肿瘤发生.pdfVIP

A Context-Specific Role for Retinoblastoma Protein- Dependent Negative Growth Control in Suppressing Mammary Tumorigenesis 1,2 3 1,2,4 Sarah M. Francis , Subrata Chakrabarti , Frederick A. Dick * 1 London Regional Cancer Program, London, Ontario, Canada, 2 Department of Biochemistry, University of Western Ontario, London, Ontario, Canada, 3 Department of Pathology, University of Western Ontario, London, Ontario, Canada, 4 Children’s Health Research Institute, London, Ontario, Canada Abstract Background: The ability to respond to anti-growth signals is critical to maintain tissue homeostasis and loss of this negative growth control safeguard is considered a hallmark of cancer. Negative growth regulation generally occurs during the G0/G1 phase of the cell cycle, yet the redundancy and complexity among components of this regulatory network has made it difficult to discern how negative growth cues protect cells from aberrant proliferation. Methodology/Principal Findings: The retinoblastoma protein (pRB) acts as the final barrier to prevent cells from entering into the cell cycle. By introducing subtle changes in the endogenous mouse Rb1 gene (Rb1DL), we have previously shown that interactions at the LXCXE binding cleft are necessary for the proper response to anti-growth signals such as DNA damage and TGF-b, with minimal effects on overall development. This disrupts the balance of pro- and anti-growth signals in mammary epithelium of Rb1DL/DL mice. Here we show that Rb1DL/DL mice are more prone to mammary tumors in the Wap- R172H p53 transgenic background indicating that negative growth regulation is important for tumor suppression in these mice. In contrast, the same defect in anti-growth control has no impac