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Carcinogenesis Advance Access published online on July 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi188
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received May 4, 2005
Revised July 13, 2005
Accepted July 15, 2005

CANCER BIOLOGY

Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis

Antonio Isidoro 1, Enrique Casado 2, Andrés Redondo 2, Paloma Acebo 1, Enrique Espinosa 2, Andrés M. Alonso 3, Paloma Cejas 2, David Hardisson 4, Juan A. Fresno Vara 2, Cristobal Belda-Iniesta 2, Manuel González-Barón 2, and José M. Cuezva 1*

1 Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, 28049 Madrid, Spain
2 Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28046 Madrid, Spain
3 Departamento de Estadística, Facultad de Ciencias Sociales y Jurídicas, Universidad Carlos III de Madrid, Getafe, 28903 Madrid, Spain
4 Servicio de Anatomía Patológica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28046 Madrid, Spain

* To whom correspondence should be addressed.
José M. Cuezva, E-mail: jmcuezva{at}cbm.uam.es


  Abstract

The aim of this study was to investigate selected proteomic markers of the metabolic phenotype of breast carcinomas as prognostic markers of cancer progression. For this purpose, a series of 101 breast carcinomas and 13 uninvolved breast samples were examined for quantitative differences in protein expression of mitochondrial and glycolytic markers. The {beta}-subunit of the mitochondrial H+-ATP synthase ({beta}-F1-ATPase) and heat shock protein 60 (Hsp 60), and the glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK) and lactate dehydrogenase (LDH) were identified by immunological techniques. Correlations of the expression level of the protein markers and of the ratios derived from them were established with the clinicopathological information of the tumors and the follow-up data of the patients. The metabolic proteome of breast cancer specimens revealed a pronounced shift towards an enhanced glycolytic phenotype concurrent with a profound alteration on the mitochondrial {beta}-F1-ATPase/Hsp60 ratio when compared to normal samples. Discriminant analysis using markers of the metabolic signature as predictor variables revealed a classification sensitivity of ~ 97%. Kaplan-Meier survival analysis showed that several of the proteomic variables significantly correlated with overall and disease-free survival of the patients. The expression level of {beta}-F1-ATPase per se allowed the identification of a subgroup of breast cancer patients with significantly worse prognosis. Multivariate Cox regression analysis indicated that tumor expression of {beta}-F1-ATPase is a significant marker independent from clinical variables to assess the prognosis of the patients. We conclude that the alteration of the mitochondrial and glycolytic proteomes is a hallmark feature of breast cancer further providing relevant markers to aid in the prognosis of breast cancer patients.


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