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

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

1.  Antonio Isidoro1,
2.  Enrique Casado2,
3.  Andrés Redondo2,
4.  Paloma Acebo1,
5.  Enrique Espinosa2,
6.  Andrés M. Alonso4,
7.  Paloma Cejas2,
8.  David Hardisson3,
9.  Juan A. Fresno Vara2,

10. Cristobal Belda-Iniesta2,

11. Manuel González-Barón2 

12. José M. Cuezva1,^*

+ Author Affiliations

1. *To whom correspondence should be addressed. Tel: +34 91 497 4866; Fax: +34 91 497 4799; Email: jmcuezva@cbm.uam.es

     Received May 4, 2005.

     Accepted July 15, 2005.

     Revision received July 13, 2005.

Abstract

Investigating specific proteome markers of the metabolic phenotype of breast carcinomas as predictive indicators of cancer progression was the goal of this work. For this, the quantitative expression of mitochondrial and glycolytic markers in a collection of 101 breast carcinomas and 13 unaffected breast tissues were compared. Immunological methods were used to identify the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, and lactate dehydrogenase, as well as the -subunit of the mitochondrial H+-ATP synthase (-F1-ATPase) and heat shock protein 60 (Hsp60). With the clinicopathological details of the tumors and the patient follow-up data, correlations of the expression level of the protein markers and of the ratios obtained from them were developed. When compared to normal samples, the metabolic proteome of breast cancer tissues showed a marked shift towards an improved glycolytic phenotype along with a significant variation on the mitochondrial -F1-ATPase/Hsp60 ratio. Using metabolic signature markers as predictor variables, discriminant analysis demonstrated a classification sensitivity of approximately 97%. Numerous proteome characteristics substantially linked with the patients’ overall and disease-free longevity, according to the Kaplan-Meier survival analysis. It was possible to identify a subgroup of breast cancer patients with a noticeably worse prognosis thanks to the expression level of -F1-ATPase. An independent marker of tumor expression of -F1-ATPase that can be used to predict a patient’s prognosis, according to multivariate Cox regression analysis. We come to the conclusion that the altered glycolytic and mitochondrial proteomes are a distinguishing characteristic of breast cancer, further supplying pertinent markers to help with the prognosis of breast cancer patients.