Abstract
Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.
Highlights
The importance of telomere structural integrity in cancer is becoming more evident [1]
In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays
[12], we reported that the addition of 5-aza-CdR alone or in combination with Trichostatin A (TSA) to the 21NT breast cancer cells affects shelterin expression
Summary
The importance of telomere structural integrity in cancer is becoming more evident [1]. Telomere dysfunction can be governed by telomere length shortening or perturbation of the protective shelterin proteins, triggering DNA-damage response, resulting in formation of chromosome end-to-end fusions and genomic instability [5]. There is a strong body of evidence suggesting that short telomeres in breast cancer cells precipitate telomere dysfunction and this may be in part related to shelterin proteins and their expression levels in breast cancer cells [11]. Our previous study revealed that in a large panel of breast cancer cell lines the expression of the shelterin proteins was down-regulated due to the promoter methylation [12]. When breast cancer cell lines were treated with 5-aza-CdR alone or in combination with trichostatin A (TSA), the levels of POT1, TIN2 and TPP1 shelterin proteins recovered to normal status [12]. We reported the first observation of small but significant elongation of telomere lengths (1 - 2 kb increases) in the breast cancer cell lines when treated with the epigenetic modifying drugs
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