Beyond demonstrating a critical role for progesterone receptor signaling in normal mammary epithelial proliferation, the progesterone receptor knockout mouse disclosed the progesterone receptor along with its effector pathways as key determinants of mammary neoplastic progression. Despite these advances, however, further progress in our mechanistic understanding of progesterones involvement in mammary morphogenesis and tumorigenesis is contingent upon defining the essential effector pathways responsible for transducing the progesterone signal into a mammary proliferative and/or pro-survival response. Toward this goal, a judiciously chosen acute progesterone treatment regimen together with microarray methods was applied to the mammary gland of the normal mouse to uncover new effectors that operate immediately downstream of the progesterone mammary signal. Examination of the resultant progesterone-responsive transcriptome disclosed inhibitor of differentiation or DNA binding 4 (Id4) as a molecular target acutely induced by progesterone in the murine mammary epithelium.
Transcriptional response of the murine mammary gland to acute progesterone exposure.
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View SamplesMost tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial (iBMK) cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity and contact inhibition, while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila.
Role of the polarity determinant crumbs in suppressing mammalian epithelial tumor progression.
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View SamplesThe recent identification of cancer stem cells (CSCs) in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. CSCs are defined by their characteristics of self-renewal, multipotentiality, and tumor initiation upon transplantation. By testing for these defining characteristics, we provide evidence for the existence of CSCs in a transgenic mouse model of glioma, S100-verbB;Trp53. In this glioma model, CSCs are enriched in the side-population (SP) cells. These SP cells have enhanced tumor-initiating capacity, self-renewal, and multipotentiality compared to non-SP cells from the same tumors. Furthermore, gene expression analysis comparing FACS-sorted cancer SP cells to non-SP cancer cells and normal neural SP cells identified 45 candidate genes that are differentially expressed in glioma stem cells. We validated the expression of two genes from this list (S100a4 and S100a6) in primary mouse gliomas and human glioma samples. Analyses of xenografted human GBM (glioblatoma multiforme) cell lines and primary human glioma tissues show that S100A4 and S100A6 are expressed in a small subset of cancer cells and that their abundance is positively correlated to tumor grade. In conclusion, this study shows that CSCs exist in a mouse glioma model, suggesting that this model can be used to study the molecular and cellular characteristics of CSCs in vivo and to further test the cancer stem cell hypothesis.
Cancer stem cells are enriched in the side population cells in a mouse model of glioma.
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View SamplesThe gene expression of bone marrow cells of mice enriched for
Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential.
Sex, Specimen part
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