xav939 and Breast-Neoplasms

Phosphoinositide 3-kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced β-catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition-induced β-catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted β-catenin nuclear accumulation in MCF-7 and MDA-MB-231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV-939, an inhibitor against β-catenin nuclear accumulation, produced an additive anti-proliferation effect against breast cancer cells. Subsequent experiments suggested β-catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti-proliferation effect of PI3K inhibitor LY294002 in MCF-7 and MDA-MB-231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Breast Neoplasms; Cell Proliferation; Chromones; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gefitinib; Heterocyclic Compounds, 3-Ring; Humans; MCF-7 Cells; Morpholines; Phosphoinositide-3 Kinase Inhibitors

The epithelial-to-mesenchymal transient (EMT) is associated with tumor metastasis. Twist is one of the key transcription factors for EMT and relates to tumor cell migration. Long non-coding RNAs (lncRNAs) have recently emerged as important regulatory molecules involved in a broad range of biological processes and complicated diseases. However, it is unknown whether a signal network and lncRNAs are involved in Twist-induced EMT program. Taking MCF10A/Twist as a model, more than 99 lncRNAs and 3164 genes are regulated in the Twist-induced EMT process using lncRNA-array and cDNA micro-array. We establish a downstream signal network associated with EMT induced by Twist using bioinformatic analysis (Gene Ontology, pathway analysis) and experimental data. A set of multiple canonical signal pathways (such as WNT, MAPK, JAK/STAT, TGF-β, mTOR, Hedgehog and P53 signaling pathways) and several lncRNAs [such as lncRNA (chr6, 26124411-26139312, +), lncRNA (chr1, 41944445-41949874, -), lncRNA (chr17, 44833874-44834830, +)] are altered in MCF10A/Twist cells. More interestingly, lncRNA (chr17, 44833874-44834830, +), lncRNA (chr17, 21142183-21156578, -), lncRNA (chr6, 26124411-26139312, +) and lncRNA (chr19, 438420-2083745, -) may be involved in regulation or activation of WNT signaling pathway in the Twist-induced EMT process. These findings first determine that Twist contributes to invasion and metastasis by inducing wide-ranging transcriptional and functional changes of lncRNAs and signal pathways in our study.

Topics: beta Catenin; Breast Neoplasms; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Epithelium; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HEK293 Cells; Heterocyclic Compounds, 3-Ring; Humans; Immunohistochemistry; Models, Biological; Nuclear Proteins; RNA, Long Noncoding; RNA, Messenger; Signal Transduction; Twist-Related Protein 1; Wnt Proteins

Constitutive Wnt signalling is characterized by excessive levels of β-catenin protein and is a frequent occurrence in cancer. APC and Axin are key components of the β-catenin destruction complex that acts to promote β-catenin degradation. The levels of Axin are in turn controlled by tankyrases, members of the PARP-family of poly-ADP-ribosylation enzymes. In colorectal cancer cells, which typically harbor APC mutations, inhibition of tankyrase activity promotes Axin stabilization and attenuates Wnt signalling. Here, we examined the effect of inhibiting tankyrases in breast cancer cells with normal APC. We show that application of the small molecule tankyrase inhibitor, XAV939 or siRNA-mediated abrogation of tankyrase expression increases Axin1 and Axin2 protein levels and attenuates Wnt-induced transcriptional responses in several breast cancer lines. In MDA-MB-231 cells, inhibiton of tankyrase activity also attenuate Wnt3a induced cell migration. Moreover, in both MDA-MB-231 and colorectal cancer cells, XAV939 inhibits cell growth under conditions of serum-deprivation. However, the presence of serum prevents this growth inhibitory effect, although inhibition of Wnt-induced transcriptional and migratory responses was maintained. These results indicate that stabilization of Axin by inhibition of tankyrases alone, may not be an effective means to block tumor cell growth and that combinatorial therapeutic approaches should be considered.

Topics: Animals; Axin Protein; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Culture Media, Conditioned; HEK293 Cells; Heterocyclic Compounds, 3-Ring; Humans; MCF-7 Cells; Mice; RNA Interference; Tankyrases; Wnt Signaling Pathway