Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis.
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 (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 beta-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 approximately 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.
Isidoro
Antonio
A
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Spain.
Casado
Enrique
E
Redondo
Andrés
A
Acebo
Paloma
P
Espinosa
Enrique
E
Alonso
Andrés M
AM
Cejas
Paloma
P
Hardisson
David
D
Fresno Vara
Juan A
JA
Belda-Iniesta
Cristobal
C
González-Barón
Manuel
M
Cuezva
José M
JM
D014408:Biomarkers, Tumor / Q000378:metabolism*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology; D018834:Chaperonin 60 / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011379:Prognosis; D020543:Proteome / Q000032:analysis; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D015996:Survival Rate
D014408:Biomarkers, Tumor; D018834:Chaperonin 60; D020543:Proteome; D007770:L-Lactate Dehydrogenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011770:Pyruvate Kinase; D006180:Proton-Translocating ATPases