Conclusion: Ro-28-2653, a selective and orally bioavailable MMPI with inhibitory activity against MMPs expressed by tumor and/or stromal cells, is a potent antitumor and antiangiogenic agent. In contrast to broad-spectrum inhibitors, the administration of Ro-28-2653 was not associated with the occurrence of adverse side effects that might hamper the therapeutic potential of these drugs.

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9);

Non-coding RNAs (ncRNA) represent 1/5 of the mammalian transcript number, and 90% of the genome length is transcribed. Many ncRNAs play a role in cancer. Among them, non-coding natural antisense transcripts (ncNAT) are RNA sequences that are complementary and overlapping to those of either protein-coding (PCT) or non-coding transcripts. Several ncNATs were described as regulating protein coding gene expression on the same loci, and they are expected to act more frequently in cis compared to other ncRNAs that commonly function in trans. In this work, 22 breast cancers expressing estrogen receptors and their paired adjacent non-malignant tissues were analyzed by strand-specific RNA sequencing. To highlight ncNATs potentially playing a role in protein coding gene regulations that occur in breast cancer, three different data analysis methods were used: differential expression analysis of ncNATs between tumor and non-malignant tissues, differential correlation analysis of paired ncNAT/PCT between tumor and non-malignant tissues, and ncNAT/PCT read count ratio variation between tumor and non-malignant tissues. Each of these methods yielded lists of ncNAT/PCT pairs that were enriched in survival-associated genes. This work highlights ncNAT lists that display potential to affect the expression of protein-coding genes involved in breast cancer pathology.

Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...