No abstract

Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary noninvasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 plays a role in controlling chromosome number but not proliferation Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Background: ⌬Np63 expression correlates with an epithelial phenotype and adverse clinical outcome. Results: ⌬Np63␣ suppressed ZEB1/2 and invasion in part by promoting miR-205 transcription, and tumor miR-205 expression is a marker of poor survival. Conclusion: ⌬Np63␣ inhibits EMT in part via miR-205. Significance: We show that ⌬Np63␣ directly regulates miR-205 and that these effects contribute to EMT suppression. The results provide important insight into the biology of lethal bladder cancer.

AR is necessary for AR nuclear export and is dominant over the NLS in the DNAbinding domain and hinge region in the absence of hormone. Our findings suggest that androgen can regulate NES AR and, subsequently, the NLS of the AR, providing a mechanism by which androgen regulates AR nuclear/ cytoplasmic shuttling. Estrogen receptor ␣ and mineralocorticoid receptor also contain functional NES, suggesting that this ligand-regulated NES is conserved among steroid receptors. Androgen receptor (AR)1 is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner (1, 2). AR is necessary for male accessory organ development and is involved in prostate cancer progression. The human AR contains 918 amino acids and consists of the N-terminal transactivation domain (1-555), DNA-binding domain (DBD) (556 -623), hinge region (624 -665), and C-terminal ligand-binding domain (LBD) (666 -918) (3). The DBD, hinge region, and LBD of AR share a high degree of homology with other steroid receptors. Intracellular localization of AR and other steroid receptors such as glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is ligand-dependent. The limit for passive diffusion across the nuclear pore complex has been suggested to fall within the range of 20 -40 kDa (4). Larger proteins such as AR, which is ϳ100 kDa in size, must be actively transported through the nuclear pore complex to enter or leave the nucleus. AR is localized to the cytoplasm in the absence of ligand and translocates into the nucleus in the presence of ligand (5-7). Likewise, nuclear AR can be exported to the cytoplasm upon ligand withdrawal (8). These observations indicate that AR contains both a nuclear localization signal (NLS) and nuclear export signal (NES) and that their activities are regulated by androgen either directly or indirectly. Because nuclear localization is necessary for steroid receptors to transactivate their target genes, the ligand-dependent nuclear import/export represents a critical mechanism by which steroids regulate the activity of their cognate receptors.The signal involved in the transport of steroid receptors from the cytoplasm to the nucleus has been studied extensively. Mutagenesis studies of the human AR have defined a bipartite NLS in the DBD and hinge region at amino acids 617-633 (9). This NLS is composed of two clusters of basic amino acids (underlined) separated by 10 amino acid residues: RKCY-EAGMTLGARKLKK. Similar NLS were found in other steroid receptors. In addition to the NLS in the DBD and hinge region, Picard and Yamamoto (10) demonstrated the existence of a ligand-dependent NLS present in the LBD of GR. When fused to ␤-galactosidase or to N-terminal fragments of the GR lacking the NLS, the LBD of GR conferred ligand-dependent nuclear localization to the fusion proteins. Similarly, a ligand-dependent NLS also exists in the LBD of AR, which is capable of inducing nuclear import in the absence of the NLS in the DBD and hinge region (11,12).Studies on sequences responsible...

Purpose We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy. Materials and Methods We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings. Results We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged. Conclusions The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.