Abberations in the Wnt

signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically.\n\nMethods: An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) HKI-272 in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative CB-839 RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays.\n\nResults: TamR cells exhibited increased Wnt signalling

as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the beta-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR VX-689 molecular weight cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT.\n\nConclusions: These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt signalling

inhibits the effects of Tamoxifen should be undertaken. As a number of small molecules targeting the Wnt pathway are currently in pre-clinical development, combinatorial treatment with endocrine agents and Wnt pathway inhibitors may be a useful therapeutic option in the future for a subset of breast cancer patients.”
“Aims Central sleep apnoea (CSA) and increased serum erythropoietin (EPO) concentration have each been associated with adverse prognosis in heart 4 failure (HF) patients. The aim of this study was to examine the relationship between nocturnal hypoxaemia due to CSA and the serum EPO concentration in patients with HF.\n\nMethods and results Heart failure subjects (n = 33) and healthy controls (n = 18) underwent polysomnography (PSG) for diagnosis of CSA and identification and quantification of hypoxaemia. Blood collection for measurement of EPO was performed immediately post-PSG. For the analysis, HF subjects were dichotomized into subgroups defined by the presence or absence of CSA and by HF severity.