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Effect of depletion of hypoxia-inducible factor (HIFs) on gene expression in MDA231-BrM2 breast cancer brain-selective metastatic cells with RNA-Seq.

ABSTRACT: Brain metastasis is a major cause of breast cancer mortality, but the molecular basis and pathological mechanisms are poorly understood. Here, we determined that integrin β3 (ITGB3) expression mediated by hypoxia-inducible factor 1 (HIF-1) plays a critical role in brain metastasis of breast cancer. Hypoxia induces HIF-1-dependent expression of ITGb3, which is required for breast cancer cell migration and invasion. Knockdown of HIF-1a or ITGB3 expression impairs the colonization of breast cancer cells to brain after injection into the cardiac left ventricle. Mechanistically, ITGB3 protein expressed by breast cancer cells was incorporated into extracellular vesicles (EVs). The ITGb3+ EVs associated with brain endothelial cells, activated vascular endothelial growth factor receptor 2 signaling, and increased endothelial permeability to facilitate metastatic colonization of the brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268804 | GEO | 2025/05/15

REPOSITORIES: GEO

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Project description:This 58 arrays are the basis of our hypoxia story published in PLoS Medicine. The cell type, oxygen tension and time points are indicated. Abstract: BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1alpha protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1alpha RNA in renal cells, and it could be diminished by reducing HIF-1alpha expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Using regression correlation

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Effect of depletion of hypoxia-inducible factor (HIFs) on gene expression in MDA231-BrM2 breast cancer brain-selective metastatic cells with RNA-Seq.

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