Carcinogenesis Advance Access originally published online on July 20, 2005
Carcinogenesis 2005 26(12):2095-2104; doi:10.1093/carcin/bgi188
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Carcinogenesis Vol.26 No.12 © Oxford University Press 2005; all rights reserved.
Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis
1 Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, 28049 Madrid, Spain, 2 Servicio de Oncología Médica and 3 Servicio de Anatomía Patológica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28046 Madrid, Spain and 4 Departamento de Estadística, Facultad de Ciencias Sociales y Jurídicas, Universidad Carlos III de Madrid, Getafe, 28903 Madrid, Spain
* To whom correspondence should be addressed. Tel: +34 91 497 4866; Fax: +34 91 497 4799; Email: jmcuezva{at}cbm.uam.es
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 ß-subunit of the mitochondrial H+-ATP synthase (ß-F1-ATPase) and heat shock protein 60 (Hsp60), and the glycolytic glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase 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 ß-F1-ATPase/Hsp60 ratio when compared with 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 ß-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 ß-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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