Abstract
Backgroud: Telomerase activity, mainly regulated by the human telomerase reverse transcriptase (hTERT) gene, plays critical roles in tumor growth and progression through the maintenance of telomere length and structure. Telomerase is elevated in most malignant tumors as well as in breast cancer, the ubiquitous expression of telomerase makes it a promising target for cancer therapy. With the goal of down regulating telomerase activity, RNA interference technology has been applied to specifically knockdown the hTERT gene expression in breast cancer cell line MCF-7 and MDA-MB- 231 and determine whether h TERT-specific RNA interference technology serve as an effective method of telomerase-based cancer therapy. Methods: Interfering p Super-retro-puro-hTERT-RNA and the control were transfected into breast cancer cell line MCF-7 and MDA-MB-231. The telomerase activity, cell proliferation, invasive ability and cell response to ultraviolet-radiation or adriamycin-chemotherapy in vitro were recorded in transfected, untransfeced and empty-transfected cells respectively. Results: Telomerase activity was successfully suppressed in transfected cells (P 0.005). Decreased expression of telomerase activity was associated with reduced cell proliferation (P 0.001), migration and invasive ability (P 0.001) and enhanced sensitivity to ultraviolet-radiation or adriamycin-chemotherapy (P 0.001). Conclusions: Telomerase activity down regulation inhibits breast cancer cell growth, impairs cell migration, invasion and sensitizes cancer cells to radiotherapy and chemotherapy. The hTERT-specific RNA interference technology combined with radio-therapy and/or chemotherapy may serve as an effective method of telomerase-based therapy in breast cancer.
Highlights
Breast cancer is the most common diagnosed malignant tumor in women and by far the second most frequent cancer in the world [1,2]
Reduction of human telomerase reverse transcriptase (hTERT) mRNA resulted in a significant decrease in telomerase activity assessed by telomeric repeat amplification protocol (TRAP) in both MCF-7 and MDA-MB-231 cell line (Figures 2(a) and (b), P < 0.005)
Telomerase activity has shown to be strongly increased in almost all human malignancies as well as in breast cancer [7,16]
Summary
Breast cancer is the most common diagnosed malignant tumor in women and by far the second most frequent cancer in the world [1,2]. In the past nearly fifty years, the treatment of breast cancer has advanced greatly in surgery as well as in chemotherapy, radiotherapy and endocrine therapy. The primary function of telomere, mainly regulated by telomerase, is to maintain the stabilization of chromosome [4,5]. Progressive shortening of telomere with cell division causes chromosomal instability and cell senescence [6]. Telomerase activity is activated in most malignant tumors including breast cancer [7]. Telomerase activity correlates with tumor aggressiveness and reflects therapy effect in breast cancer [8] and is believed as a prognostic marker
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