Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis.
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.
Gubin
Matthew M
MM
Department of Surgery, University of Missouri, Columbia, Missouri, USA.
Calaluce
Robert
R
Davis
J Wade
JW
Magee
Joseph D
JD
Strouse
Connie S
CS
Shaw
Daniel P
DP
Ma
Lixin
L
Brown
Ashley
A
Hoffman
Timothy
T
Rold
Tammy L
TL
Atasoy
Ulus
U
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
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