|Title:||Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/β-catenin pathway||Authors:||Chang P.-H.
|Issue Date:||2012||Journal Volume:||72||Journal Issue:||18||Start page/Pages:||4652-4661||Source:||Cancer Research||Abstract:||
Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes. ?2012 AACR.
|ISSN:||0008-5472||DOI:||10.1158/0008-5472.CAN-12-0877||SDG/Keyword:||beta catenin; cyclin D1; Myc protein; phosphatidylinositol 3 kinase; protein kinase B; roundabout receptor; roundabout receptor 1; Slit2 protein; unclassified drug; Akt signaling pathway; animal experiment; animal model; animal tissue; article; beta catenin signaling pathway; breast cancer; cancer cell; carcinogenesis; cell heterogeneity; controlled study; down regulation; enzyme activation; fibroblast; gene expression profiling; gene translocation; human; human cell; human tissue; immunofluorescence; mouse; nonhuman; PI3K signaling pathway; priority journal; protein expression; protein phosphorylation; protein protein interaction; signal transduction; tumor growth; tumor microenvironment; tumor volume; Animals; beta Catenin; Breast Neoplasms; Cell Line, Tumor; Disease Progression; Female; Fibroblasts; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Mice, SCID; Nerve Tissue Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Receptors, Immunologic; Signal Transduction; Tumor Microenvironment
|Appears in Collections:||病理學科所|
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