التفاصيل البيبلوغرافية
| العنوان: |
Lactate Dehydrogenase-B Is Silenced by Promoter Methylation in a High Frequency of Human Breast Cancers. |
| المؤلفون: |
Brown, Nicola J.1, Higham, Sue E.1, Perunovic, Branko2, Arafa, Mohammad2, Balasubramanian, Sabapathy1, Rehman, Ishtiaq3 i.rehman@sheffield.ac.uk |
| المصدر: |
PLoS ONE. Feb2013, Vol. 8 Issue 2, p1-8. 8p. |
| مصطلحات موضوعية: |
*BREAST cancer, *LACTATE dehydrogenase, *GENE silencing, *PROMOTERS (Genetics), *METHYLATION, *OXIDATIVE stress, *PHOSPHORYLATION, *CANCER cells |
| مستخلص: |
Objective: Under normoxia, non-malignant cells rely on oxidative phosphorylation for their ATP production, whereas cancer cells rely on Glycolysis; a phenomenon known as the Warburg effect. We aimed to elucidate the mechanisms contributing to the Warburg effect in human breast cancer. Experimental design: Lactate Dehydrogenase (LDH) isoenzymes were profiled using zymography. LDH-B subunit expression was assessed by reverse transcription PCR in cells, and by Immunohistochemistry in breast tissues. LDH-B promoter methylation was assessed by sequencing bisulfite modified DNA. Results: Absent or decreased expression of LDH isoenzymes 1-4, were seen in T-47D and MCF7 cells. Absence of LDH-B mRNA was seen in T-47D cells, and its expression was restored following treatment with the demethylating agent 5'Azacytadine. LDH-B promoter methylation was identified in T-47D and MCF7 cells, and in 25/ 25 cases of breast cancer tissues, but not in 5/ 5 cases of normal breast tissues. Absent immuno-expression of LDH-B protein (<10% cells stained), was seen in 23/ 26 (88%) breast cancer cases, and in 4/8 cases of adjacent ductal carcinoma in situ lesions. Exposure of breast cancer cells to hypoxia (1% O2), for 48 hours resulted in significant increases in lactate levels in both MCF7 (14.0 fold, p = 0.002), and T-47D cells (2.9 fold, p = 0.009), but not in MDA-MB-436 (-0.9 fold, p = 0.229), or MCF10AT (1.2 fold, p = 0.09) cells. Conclusions: Loss of LDH-B expression is an early and frequent event in human breast cancer occurring due to promoter methylation, and is likely to contribute to an enhanced glycolysis of cancer cells under hypoxia. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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