title: Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis.
abstract: Interactions between RNA binding proteins (RBPs) and genes are not well understood, especially in regulation of angiogenesis. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, facilitating their translation into protein and has been hypothesized to be a tumor-maintenance gene. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR controls the expression of multiple genes involved in angiogenesis including VEGFα, HIF1α and thrombospondin 1 (TSP1). We investigated the role of HuR in estrogen receptor negative (ER(-)) breast cancer. MDA-MB-231 cells with higher levels of HuR have alterations in cell cycle kinetics and faster growth. Unexpectedly, HuR overexpression significantly interfered with tumor growth in orthotopic mouse models. The putative mechanism seems to be an anti-angiogenetic effect by increasing expression of TSP1 but also surprisingly, downregulating VEGF, a target which HuR normally increases. Our findings reveal that HuR may be regulating a cluster of genes involved in blood vessel formation which controls tumor angiogenesis. An approach of modulating HuR levels may overcome limitations associated with monotherapies targeting tumor vessel formation.
authors: Department of Surgery, University of Missouri, Columbia, Missouri, USA.
authors: Matthew M
authors: MM
authors: Gubin
authors: Robert
authors: R
authors: Calaluce
authors: J Wade
authors: JW
authors: Davis
authors: Joseph D
authors: JD
authors: Magee
authors: Connie S
authors: CS
authors: Strouse
authors: Daniel P
authors: DP
authors: Shaw
authors: Lixin
authors: L
authors: Ma
authors: Ashley
authors: A
authors: Brown
authors: Timothy
authors: T
authors: Hoffman
authors: Tammy L
authors: TL
authors: Rold
authors: Ulus
authors: U
authors: Atasoy
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; C481348:SPZ1 protein, human; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A