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

Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

The ROS1 kinase is an oncogenic driver in non-small-cell lung cancer (NSCLC). Fusion events involving the ROS1 gene are found in 1%–2% of NSCLC patients and lead to deregulation of a tyrosine kinase–mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of NSCLC, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (&lt;50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ROS1 kinase with crizotinib is associated with increased progression-free survival (PFS) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged NSCLC, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced NSCLC, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop

Her-2 Immunohistochemical Expression in Oral Squamous Cell Carcinomas is Associated with Polysomy of Chromosome 17, Not Her-2 Amplification

Based on the prognostic role of Her-2 amplification and protein overexpression in breast cancer, various studies have been performed in oral squamous cell carcinomas (OSCC) with inconsistent results. As in invasive breast carcinomas Her-2 overexpression has been related to an increased number of chromosome 17 copies, a common chromosomal alteration in OSCC, we evaluated the association between polysomy 17 and Her-2 protein expression in a series of primary OSCC. Forty-one incisional biopsies of primary OSCC were included in the study. Protein expression was evaluated immunochistochemically with CB11 mouse monoclonal anti-human antibody. The reaction was arbitrarily characterized as absent, faint, moderate, and strong, and staining pattern as cytoplasmic and membranous. Positive cases were analyzed by chromogenic in situ hybridisation (CISH) to access Her-2 status. The association between polysomy 17 and Her-2 expression was checked by Fisher’s exact test. Four cases were negative and 37 cases were positive for Her-2. Staining was faint in 15 cases and moderate in 22 cases. CISH showed that all cases with faint staining were diploid, while from the cases with moderate staining 10 were diploid and 12 polysomic for chromosome 17. Thirteen cases showed purely cytoplasmic staining, while in 24 there were areas of both cytoplasmic and membranous staining. There was a statistically significant correlation between intensity of the reaction and polysomy 17 (P = 0.0036), in particular for cases with both cytoplasmic and membranous staining (P = 0.0128). In some OSCC Her-2 immunohistochemical expression may be associated with chromosome 17 polysomy and not Her-2 amplification