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Carcinogenesis Advance Access published online on August 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn185
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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. Ortega1,2, Sandra Sala1, Enrique Espinosa3, Manuel González-Barón3 and José M. Cuezva1,2,4

1 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM
2 CIBER de Enfermedades Raras (CIBERER)
3 Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28049 Madrid, Spain

4 Author to whom correspondence should be addressed: Prof. José M. Cuezva, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain. Phone: 34 911 964 618 Fax: 34 911 964 420. E-mail: jmcuezva{at}cbm.uam.es

Down-regulation 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 post-transcriptional mechanisms. Herein, we pursue the identification of β-F1-ATPase mRNA binding proteins (β-RNABPs) 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-RNABP that interacts with the 3'UTR of the transcript. Subcellular fractionation and high-resolution immunoelectron microscopy revealed the co-fractionation 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, over-expression experiments and shRNA-mediated silencing of HuR in human HEK 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.

Received April 24, 2008; revised July 24, 2008; accepted August 3, 2008.


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[Abstract] [Full Text] [PDF]


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