HIF-1a and target genes as metabolic biomarkers in Mexican women with breast cancer.

Abstract

e21063 Background: Breast cancer is the principal malignancy in Mexican women. Breast neoplasias develop chaotic and fragile neovasculature originating intermittent hypoxia which in turn, leads to an adaptive response coordinated by the transcriptional factor HIF-1a (hypoxia-inducible factor-1a). In the present work the expression of HIF-1a was analyzed in different female breast cancer biopsies in order to determine the relationship between HIF-1a expression and cancer prognosis. To determine the functional role of HIF-1a, proteomic and kinetic analysis of several well-established HIF-1 targets such as the glycolytic proteins glucose transporters (GLUT1), hexokinase (HKII), and lactate dehydrogenase (LDH-A) were also determined. In addition, to evaluate the role of HIF-1a expression on mitochondrial function, content of mitochondrial enzymes were also assayed. Methods: Twenty tru-cut biopsies were obtained from female patients (30-45 years old) without previous clinical treatment. After patho-histological assessment of breast cancer incidence, samples were processed by Western-blot analysis (for proteomic analysis) and for enzyme activity determination. Results: Significant increased content of HIF-1a was determined in all human solid tumor biopsies analyzed. In consequence, enhanced GLUT1, HKII and LDH-A contents and activities (12 and 314 mU/mg protein for HK and LDH, respectively) were also detected. On the contrary, mitochondrial enzymes (cytochrome c oxidase, ATP/ADP translocator, glutaminase-K and 2-oxoglutarate dehydrogenase) were not detected, whereas ATP synthase content significantly increased in all analyzed samples. Conclusions: These results clearly indicated that HIF-1a, together with their target glycolytic genes and possibly the mitochondrial enzyme ATP synthase, may be useful to depict a breast cancer metabolic marker pattern.