Journal Article

HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence

Álvaro D. Ortega, Sandra Sala, Enrique Espinosa, Manuel González-Barón and José M. Cuezva

in Carcinogenesis

Volume 29, issue 11, pages 2053-2061
Published in print November 2008 | ISSN: 0143-3334
Published online August 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn185
HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence

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Downregulation of the catalytic subunit of the mitochondrial H+-ATP synthase (β-F1-ATPase) is a hallmark of many types of cancer. The expression of β-F1-ATPase is stringently controlled by posttranscriptional mechanisms. Herein, we pursue the identification of β-F1-ATPase messenger RNA-binding proteins (β-mRNABPs) that interact and could define the bioenergetic phenotype of the cancer cell in order to establish its relevance as markers of breast cancer progression. RNA immunoprecipitation and RNA affinity chromatography identify HuR as a β-mRNABP that interacts with the 3′-untranslated region of the transcript. Subcellular fractionation and high-resolution immunoelectron microscopy revealed the cofractionation and presence of HuR in subcellular structures associated to liver mitochondria. Analysis of the expression level of HuR in a cohort of breast carcinomas shows its association with the degree of alteration of the bioenergetic phenotype of the tumor. Moreover, HuR expression is shown to be an independent marker of breast cancer prognosis. A low tumor expression of HuR predicts a higher risk of disease recurrence in early stage breast cancer patients as assessed by clinical and bioenergetic markers of prognosis, strongly supporting the incorporation of HuR as an additional marker for the follow-up of these patients. Mechanistically, overexpression experiments and short hairpin RNA-mediated silencing of HuR in human embryonic kidney and HeLa cells indicate that HuR is not regulating β-F1-ATPase expression. Overall, the participation of additional RNA-binding proteins in controlling β-F1-ATPase expression and therefore in defining the bioenergetic signature of the cancer cell is expected.

Journal Article.  7484 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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