Troglitazone suppresses telomerase activity independently of PPARγ in estrogen-receptor negative breast cancer cells

<p>Abstract</p> <p>Background</p> <p>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 (PPARγ). However, its effect on telomerase regulation in breast cancer has not been investigated.</p> <p>Methods</p> <p>In this study, we investigated the effect of the PPARγ 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 PPARγ expression silenced using shRNA interference.</p> <p>Results</p> <p>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 PPARγ. In agreement with this result, we found no correlation between PPARγ and hTERT mRNA transcript levels in breast cancer patients. Statistical significance was determined using Pearson correlation and the paired Student's <it>t </it>test.</p> <p>Conclusions</p> <p>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.</p

Telomere Length on Chromosome 17q Shortens More than Global Telomere Length in the Development of Breast Cancer

It is known that total telomere length is shorter in invasive breast cancer than in normal breast tissue but the status of individual telomere lengths has not been studied. Part of the difficulty is that usually telomere length in interphase cells is measured on all chromosomes together. In this study we compared normal breast epithelium, duct carcinoma in situ (DCIS), and invasive duct carcinoma (IDC) from 18 patients. Telomere length was specifically measured on chromosome 17q and was found to be shorter in DCIS and IDC than in normal breast epithelial cells, with more heterogeneity in telomere length in DCIS associated with IDC than in DCIS alone. More importantly, we found that the shortening of telomere on chromosome 17q is greater than the average shortening of all telomeres. This finding indicates that telomere shortening is not simply the result of the end replication problem; otherwise, all telomeres should be subjected to the same rate of telomere shortening. It seems there are mechanisms that preferentially erode some telomeres more than others or preferentially protect some chromosome ends. Our results suggest that the increased level of telomere shortening on 17q may be involved in chromosome instability and the progression of DCIS

Incidence of chronic myeloid leukemia in Calgary, Alberta, Canada

Abstract Objective The epidemiology of chronic myeloid leukemia is shifting due to the aging global population and the recent discovery and availability of targeted treatment options. This study provides recent data regarding the incidence of CML in Calgary, a major Canadian city. Data from patients diagnosed with CML by bone marrow sample analysis from 2011 to 2015 were collected from the database of the sole centralized cytogenetics facility in service of Calgary and its surrounding area. Results With an average of 10.2 newly diagnosed cases per year in Calgary from 2011 to 2015, the incidence rate was calculated to be 0.75 cases per 100,000 person-years (95% CI 0.57–0.99). With age standardization, the incidence was 0.87 cases per 100,000 person-years (95% CI 0.82–0.91) for the Canadian population, which was low compared to other developed Western nations. The highest incidence rates were observed in the older patient categories, however there was a broad age distribution for incident cases and the median age at diagnosis was 48. There was a general male bias for CML most pronounced at the younger ages. Our description of CML incidence will help to inform healthcare planners amidst the dramatically altered treatment of this hematological neoplasm

Incidence of myeloproliferative neoplasms in Calgary, Alberta, Canada

Abstract Objective The incidence of the combined myeloproliferative neoplasms (MPNs) was determined for a major Canadian city. Retrospective cases of MPN diagnoses (essential thrombocythemia, polycythemia vera, and primary myelofibrosis) between 2011 to 2015 were retrieved from the Southern Alberta Cancer Cytogenetics Laboratory’s database at Alberta Public Laboratories. Results An incidence rate of 2.05 cases per 100,000 person-years (95% CI 1.73–2.41) was determined, giving an age-standardized Canadian incidence of 2.71 cases per 100,000 person years (95% CI 2.63–2.78). MPN diagnoses occurred at a wide age range of 8–93 (median 66) and an age-dependent increase in incidence. Incidence rates for the MPNs are first reported here for a Canadian population

The incidence of acute myeloid leukemia in Calgary, Alberta, Canada: a retrospective cohort study

Abstract Background The incidence rate of acute myeloid leukemia (AML) was determined in the Calgary Metropolitan Area, a major Canadian city. Methods Data from all patients diagnosed with AML between January 1, 2011 and December 31, 2015 were retrieved from a single, centralized cancer cytogenetics laboratory for bone marrow samples, the sole diagnostic facility of its kind in Southern Alberta. Results The calculated incidence rate was 2.79 cases per 100,000 person-years with a median age of 60, slightly lower than previously published data. The age-standardized incidence rate for Canada was 3.46 cases per 100,000 person-years. The higher value is reflective of Calgary’s younger population compared to the rest of Canada. Higher male incidence and greatest incidence occurring at approximately the age of 85 is similar to data from other developed countries. The lower incidence rates and median age of diagnosis, in comparison with that of other high-income nations, may be due to differences in the proportion of aging citizens in the population. Conclusion This is the first published incidence rate of acute myeloid leukemia (AML) in Canada across all age groups

Incidence of acute lymphocytic leukemia in Calgary, Alberta, Canada: a retrospective cohort study

Abstract Objective Acute lymphocytic leukemia (ALL) is a rare malignant neoplasm that develops from abnormal lymphoid stem cells. ALL incidence is highest among children and declines towards adolescence. There is limited data on the epidemiology of ALL, especially in Canada. This retrospective cohort study used patient data from the Calgary Laboratory Services Cancer Cytogenetics Laboratory to report the incidence rate of ALL in Calgary, Alberta, Canada. New cases of ALL were identified for the 5-year period of January 1, 2011 until December 31, 2015. Reported incidence rates were categorized by sex and age groups, and age-standardized to the Canadian population. Results There were an average of 11.4 new cases of ALL diagnosed per year between 2011 and 2015. The total incidence rate per 100,000 person-years was 0.84. Incidence rates peaked in children aged 0–4 with 7.55 and 3.32 cases per 100,000 person-years for males and females, respectively. The median age of diagnosis was 8 years. Incidence rates were generally lowest for adults aged 20 and over. The ratio of males to females diagnosed with ALL was 1.59. Overall, the recent incidence of ALL in Calgary is comparatively low with a preference for males and children below 5 years of age