Dataset Information

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.

ABSTRACT: Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell-like features.

SUBMITTER: McCoy EL

PROVIDER: S-EPMC2735909 | biostudies-other | 2009 Sep

REPOSITORIES: biostudies-other

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Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.

McCoy Erica L EL Iwanaga Ritsuko R Jedlicka Paul P Abbey Nee-Shamo NS Chodosh Lewis A LA Heichman Karen A KA Welm Alana L AL Ford Heide L HL

The Journal of clinical investigation 20090824 9

Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive ma ...[more]

PMID: 19726883

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Project description:Vaccinia-related kinase 1 (VRK1) is a pro-proliferative nuclear kinase. Mice engrafted with VRK1-depleted MDA-MB-231 breast cancer cells have been shown to develop fewer distal metastases than controls, suggesting VRK1 might play a role in cell migration, invasion, and/or colonization. In work described herein, we investigated the impact of VRK1 overexpression on human mammary epithelial cells. In 2D culture, VRK1 overexpression diminishes cell migration and invasion and impairs the migration-associated processes of cell spreading and cytoskeletal rearrangement. VRK1-overexpressing cells show reduced accumulation of the mesenchymal marker vimentin and increased accumulation of the epithelial markers E-cadherin and claudin-1. VRK1 overexpression also leads to reduced levels of the transcriptional repressors snail, slug, and twist1. Cumulatively, these data indicate that VRK1 overexpression augments the epithelial properties of both MCF10a and MDA-MB-231 cells. We further studied the impact of VRK1 on the epithelial properties of MCF10a cells in 3D matrigel culture, in which cells proliferate and form epithelial sheets that mature into hollow spherical acini. VRK1 overexpression significantly accelerates the initial stages of cell proliferation, leading to larger acini that nevertheless differentiate and mature. Our analysis of human tumor tissue microarrays (TMAs) revealed that VRK1 protein levels are higher in lymph node metastases than in patient-matched mammary tumors. Using public databases, we determined that VRK1 is among the top 10% of overexpressed transcripts in multiple subtypes of invasive breast cancer, and that high levels of VRK1 expression are correlated with decreased relapse-free survival. In sum, overexpression of VRK1, by regulating the transcription repressors snail, slug, and twist1, can promote a mesenchymal-to-epithelial transition (MET) in cell culture. VRK1-mediated MET might facilitate the colonization of distal sites by metastatic breast cancer cells, providing some insight into the frequent association of VRK1 overexpression with breast malignancies and the correlation between VRK1 overexpression and poor clinical outcome.

Dataset Information

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.

Publications

Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.

Similar Datasets

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