Troglitazone suppresses telomerase activity independently of PPARgamma in estrogen-receptor negative breast cancer cells.
BACKGROUND
Breast cancer is one the highest causes of female cancer death worldwide. Many standard chemotherapeutic agents currently used to treat breast cancer are relatively non-specific and act on all rapidly dividing cells. In recent years, more specific targeted therapies have been introduced. It is known that telomerase is active in over 90% of breast cancer tumors but inactive in adjacent normal tissues. The prevalence of active telomerase in breast cancer patients makes telomerase an attractive therapeutic target. Recent evidence suggests that telomerase activity can be suppressed by peroxisome proliferator activated receptor gamma (PPARgamma). However, its effect on telomerase regulation in breast cancer has not been investigated.


METHODS
In this study, we investigated the effect of the PPARgamma ligand, troglitazone, on telomerase activity in the MDA-MB-231 breast cancer cell line. Real time RT-PCR and telomerase activity assays were used to evaluate the effect of troglitazone. MDA-MB-231 cells had PPARgamma expression silenced using shRNA interference.


RESULTS
We demonstrated that troglitazone reduced the mRNA expression of hTERT and telomerase activity in the MDA-MB-231 breast cancer cell line. Troglitazone reduced telomerase activity even in the absence of PPARgamma. In agreement with this result, we found no correlation between PPARgamma and hTERT mRNA transcript levels in breast cancer patients. Statistical significance was determined using Pearson correlation and the paired Student's t test.


CONCLUSIONS
To our knowledge, this is the first time that the effect of troglitazone on telomerase activity in breast cancer cells has been investigated. Our data suggest that troglitazone may be used as an anti-telomerase agent; however, the mechanism underlying this inhibitory effect remains to be determined.
Rashid-Kolvear
Fariborz
F
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Taboski
Michael A S
MA
Nguyen
Johnny
J
Wang
Dong-Yu
DY
Harrington
Lea A
LA
Done
Susan J
SJ
D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D002839:Chromans; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; C509186:TERT protein, human; D019098:Telomerase; D000077288:Troglitazone