تلومراز و سرطان پستان

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Title

Telomerase and Breast Cancer

English Abstract

Introduction: Telomerase is a ribonucleoprotein that compensates the shortening of the ends of eukaryotic chromosomes occuring during the cell cycle. Telomerase consists of two fundamental components, an RNA component (in humans, hTR or hTERc_ and a reverse transcriptase component (hTERT). hTR gene does not have any intron and requires specific strategies to determine its expression. Methods: Tumor samples from 46 patients with primary invasive breast cancer and patients with benign tumors were collected. The TRAP assay was used to detect telomerase activity. In order to detect low activity telomerase in samples with a negative telomerase activity on initial TRAP assay, a new strategy which was using the Re-PCR performance on TRAP products was evaluated. The expression of hTERT and its alternate splice variants were detected by RT-PCR. RT-PCR on cDNA and DNased cDNA samples and control groups was used to detect the expression of hTR, GAPDH and PGM1 genes (as housekeeping). Results: Performance of the standard TRAP assay demonstrated telomerase activity in 30 (62.5%0 out of 48 samples, but by using a repeat PCR (re-PCR) strategy, 6 (33%) out of 18 samples with an initial negative result had telomerase activity after re-PCR. The hTERT expression was revealed in 39 (81.3%). DNA contamination was detected in 34 (70.8%) of RNA samples. Without performing DNase treatment, 47 (97.9%) of all samples showed hTR expression, but with the application of this strategy, hTR expression decreased from 98% to 66.7%. In spite of finding no significant association between telomerase activity and hTERT expression, it was found by hTR expression (P<0.001). At all, telomerase or its subunits were statistically correlated with age at diagnosis, the tumor size, low grade of tumors and the tumors stage. The telomerase activity was found in 92.3% (12/13) of F/F cases and this finding was revealed to be in 87.5% (7/8) of hTR+ cases. In 3 cases with benign tumors, hTERT activity was detected in 2 (66.7%), but none of them had telomerase activity on hTR expression. Discussion: The frequencies of telomerase activiation and hTERT gene expression detected in this study were concordant with the previous investigations. However, by using the DNase treatment strategy, against the previous reports, the hTR expression was not found to be present in all of samples. Therefore, the chance of obtaining the association between hTR expression and telomerase activity, hTERT expression, and histopathologic indicators was created. Considering the alternate splicing of hTERT, the finding significant association between activity of telomerase and F/F variant in hTR- cases, as well as detection of this enzyme actinity in 87.5% of F/F, in hTR+ cases, indicate the power of full length transcript to create a complete activity. The telomerase activity found in 82.3% of cases with full length (F/?) and 92% of such cases which had hTR expression supported the effect of F variant on the telomerase activation. Conclusion: Introducing the correlations of prognostic indicators and genetic alterations could be useful for predicting the tumor progression, especially metastasis of it. the more in vitro investigations on the basis of comparing full length with deleted variants of hTERT RNA to form the active and stable telomerase enzyme will be considered.

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