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PDF file 97K, List of the 89 Wnt pathway selected genes

PDF file 161K, A simplified representation of the three different Wnt signalling pathways: the canonical pathway, the planar cell polarity pathway, and the Wnt/calcium pathway. In the absence of Wnt ligand, the 'destruction complex' composed of the core proteins Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase-3 (GSK3) rapidly phosphorylates cytosolic beta-catenin, targeting it for subsequent proteasome-mediated destruction. Binding of Wnt to Frizzled (FZD) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates the cytosolic protein Dishevelled (DVL), leading to inhibition of the destruction complex. The resulting accumulated beta-catenin can then translocate to the nucleus to activate Wnt-responsive target genes regulated by lymphoid enhancer factor (LEF) and T cell factor (TCF) family transcription factors, leading to various cellular effects. The secreted inhibitor Dickkopf (DKK) can antagonize Wnt signalling by competitively binding to LRP5/6. Secreted FZD-related proteins (SFRPs) and Wnt inhibitory factor (WIF) are thought to antagonize Wnt signalling by sequestering Wnt ligand in the extracellular space. Binding of Wnt isoforms to FZD can trigger beta-catenin-independent downstream signalling events, other so-called non-canonical Wnt pathways that do not require the transcriptional activity of beta-catenin. One branch of non-canonical pathways involves the activation of RHO and RAC small G proteins to regulate the actin cytoskeleton. DVL-associated activator of morphogenesis 1 (DAAM1), when complexed with DVL and RHO, acts through the regulation of RHO-associated protein kinases (ROCK) and the DVL-RAC GTPase complex to affect actin remodelling. Another branch, when activated, is defined by a phospholipase C (PLC)-mediated increase in intracellular Ca2+ levels and Ca2+ fluxes that lead to the activation of Ca2+/calmodulin-dependent protein kinase (CaMK), protein kinase C (PKC), and nuclear factor of activated T cells (NFAT)

Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies.Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial–mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines.Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann–mesenchymal transition.Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358–71. ©2013 AACR.

Immunological dysregulation in asthma is associated with changes in exposure to microorganisms early in life. Gammaherpesviruses (γHVs), such as Epstein-Barr virus, are widespread human viruses that establish lifelong infection and profoundly shape host immunity. Using murid herpesvirus 4 (MuHV-4), a mouse γHV, we show that after infection, lung-resident and recruited group 2 innate lymphoid cells (ILC2s) exhibit a reduced ability to expand and produce type 2 cytokines in response to house dust mites, thereby contributing to protection against asthma. In contrast, MuHV-4 infection triggers GM-CSF production by those lung ILC2s, which orders the differentiation of monocytes (Mos) into alveolar macrophages (AMs) without promoting their type 2 functions. In the context of γHV infection, ILC2s are therefore essential cells within the pulmonary niche that imprint the tissue-specific identity of Mo-derived AMs and shape their function well beyond the initial acute infection.

The song control nucleus HVC of songbirds has emerged as a widespread model system to study adult neurogenesis and the factors that modulate the incorporation of new neurons, including seasonal state, sex differences or sex steroid hormone concentrations. However, the specific function of these new neurons born in adulthood remains poorly understood. We implemented a new procedure based on focal X-ray irradiation to deplete neural progenitors in the ventricular zone adjacent to HVC and study the functional consequences. A 23 Gy dose depleted by more than 50 percent the incorporation of BrdU in neural progenitors, a depletion that was confirmed by a significant decrease in doublecortin positive neurons. This depletion of neurogenesis significantly increased the variability of testosterone-induced songs in females and decreased their bandwidth. Expression of the immediate early gene ZENK (a.k.a. egr-1) in secondary auditory areas of the telencephalon that respond to song was also inhibited. These data provide compelling evidence that new neurons in HVC play a role in both song production and perception and that X-ray focal irradiation represents an excellent tool to advance our understanding of adult neurogenesis.

Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5 Gy) was done in male 8- to 12-wk-old C57bl/6 mice using a small animal radiation therapy device. Left renal I/R was performed by clamping the renal pedicles for 30 min, with simultaneous right nephrectomy, at 7, 14, and 28 days postirradiation. The renal reperfusion lasted 48 h. Following I/R, blood urea nitrogen (BUN) and serum creatinine (SCr) levels were lower in preirradiated mice compared with controls; so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in preirradiated mice. The numbers of proliferating cell nuclear antigen (PCNA)-, cluster of differentiation molecule 11b (CD11b)-, and cell surface glycoprotein F4/80-positive cells in the renal parenchyma post-I/R were reduced in preirradiated versus control groups. Such IPC was significantly observed as early as

AimsDietary cholesterol and palmitic acid are risk factors for cardiovascular diseases (CVDs) affecting the arteries and the heart valves. The ionizing radiation that is frequently used as an anticancer treatment promotes CVD. The specific pathophysiology of these distinct disease manifestations is poorly understood. We, therefore, studied the biological effects of these dietary lipids and their cardiac irradiation on the arteries and the heart valves in the rabbit models of CVD.Methods and ResultsCholesterol-enriched diet led to the thickening of the aortic wall and the aortic valve leaflets, immune cell infiltration in the aorta, mitral and aortic valves, as well as aortic valve calcification. Numerous cells expressing α-smooth muscle actin were detected in both the mitral and aortic valves. Lard-enriched diet induced massive aorta and aortic valve calcification, with no detectable immune cell infiltration. The addition of cardiac irradiation to the cholesterol diet yielded more calcification and more immune cell infiltrates in the atheroma and the aortic valve than cholesterol alone. RNA sequencing (RNAseq) analyses of aorta and heart valves revealed that a cholesterol-enriched diet mainly triggered inflammation-related biological processes in the aorta, aortic and mitral valves, which was further enhanced by cardiac irradiation. Lard-enriched diet rather affected calcification- and muscle-related processes in the aorta and aortic valve, respectively. Neutrophil count and systemic levels of platelet factor 4 and ent-8-iso-15(S)-PGF2α were identified as early biomarkers of cholesterol-induced tissue alterations, while cardiac irradiation resulted in elevated levels of circulating nucleosomes.ConclusionDietary cholesterol, palmitic acid, and cardiac irradiation combined with a cholesterol-rich diet led to the development of distinct vascular and valvular lesions and changes in the circulating biomarkers. Hence, our study highlights unprecedented specificities related to common risk factors that underlie CVD.

Temperate-zone birds display marked seasonal changes in reproductive behaviors and the underlying hormonal and neural mechanisms. These changes were extensively studied in canaries (Serinus canaria) but differ between strains. Fife fancy male canaries change their reproductive physiology in response to variations in day length but it remains unclear whether they become photorefractory (PR) when exposed to long days and what the consequences are for gonadal activity, singing behavior and the associated neural plasticity. Photosensitive (PS) male birds that had become reproductively competent (high song output, large testes) after being maintained on short days (SD, 8 L:16D) for 6 months were divided into two groups: control birds remained on SD (SD-PS group) and experimental birds were switched to long days (16 L:8D) and progressively developed photorefractoriness (LD-PR group). During the following 12 weeks, singing behavior (quantitatively analyzed for 3 × 2 hours every week) and gonadal size (repeatedly measured by CT X-ray scans) remained similar in both groups but there was an increase in plasma testosterone and trill numbers in the LD-PR group. Day length was then decreased back to 8 L:16D for LD-PR birds, which immediately induced a cessation of song, a decrease in plasma testosterone concentration, in the volume of song control nuclei (HVC, RA and Area X), in HVC neurogenesis and in aromatase expression in the medial preoptic area. These data demonstrate that Fife fancy canaries readily respond to changes in photoperiod and display a pattern of photorefractoriness following exposure to long days that is associated with marked changes in brain and behavior.

Background and Aims Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. The right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8) at Days 7-14-21-28 post irradiation. Experiment 3: Following the same protocol of renal I/R at Day14, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 per group): 1/ bilateral pre-irradiation; 2/ bilateral pre-irradiation and gavage with Sunitinib from Day2 to Day13; 3/ control group without irradiation or gavage. Results Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) showed an increase at both mRNA (real-time qPCR) and protein (immuno-staining) levels in irradiated kidneys compared to controls (p Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p Experiment 3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, the serum levels of BUN and SCr were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p Conclusion Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal pre-irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP.

Introduction L’irradiation corporelle induit un conditionnement ischemique renal (CIR) chez la souris. Les mecanismes cellulaires sont meconnus, hormis un possible role de la neo-angiogenese. Description Dans cette etude, nous etudions les voies impliquees dans l’irradiation renale. Ensuite, nous analysons l’impact fonctionnel sur les reins avant ischemie renale/reperfusion (I/R). Enfin, nous testons si l’inhibition de l’angiogenese par le Sunitinib empeche le CIR associe a l’irradiation. Methodes Exp1. Une irradiation renale(8 Gy) est realisee chez des C57bl/6 mâles (n = 10). Un mois plus tard, l’ARN renal total est extrait pour un RNAseq comparatif. Exp2. A 7–14–28 jours post-irradiation renale, les reins droits sont nephrectomises et les reins gauches subissent une ischemie (30 min)/reperfusion (48 h) (n = 8/timing). Exp3. Suivant le meme protocole d’I/R a j14, 3 groupes sont compares (n = 8/groupe) : – irradiation ; – irradiation et gavage au sunitinib de j2 a j13 ; – groupe temoin sans irradiation ni gavage. Resultats Exp1. RNAseq montre une up-regulation des voies de l’angiogenese. L’expression de VEGF et CD31 est significativement augmentee au niveau ARNm et proteique dans les reins irradies. Exp2. Apres I/R a j14 post-irradiation, les taux seriques d’uree (BUN) et de creatinine (SCr) sont plus faibles chez les souris irradiees par rapport aux temoins (BUN : 86,2 ± 6,8 vs 454,5 ± 27,2 mg/dL ; SCr : 0,1 ± 0,01 vs 1,7 ± 0,2 mg/dL, p Fig. 1 ). Conclusion L’irradiation renale induit l’activation de l’angiogenese chez la souris et est associee a un CIR, avec fonction renale preservee et inflammation attenuee post-I/R. L’exposition au sunitinib post-irradiation empeche ce CIR.

To better define the role of FOXO1 and FOXO3 transcriptional factors in breast carcinogenesis, we performed a comparative study of their expression at both the RNA and protein levels in a series of human breast tumors. We used qRT-PCR assay to quantify mRNA expression and Reverse Phase Protein Arrays (RPPA) to quantify protein expression in 218 breast tumors from patients with known clinical/pathological status and outcome. Weak correlations were observed between mRNA and protein expressions for both FOXO1 and FOXO3 genes. High expression of FOXO3 protein, but not FOXO1 protein, was a good prognostic marker, negatively correlated with KI67 and markers of activity of the PI3K/AKT/mTOR oncogenic pathway, and positively correlated with p53, a marker of apoptosis. Moreover, FOXO3 protein expression, but not FOXO1 protein expression, was also negatively correlated with various proteins involved in different DNA repair mechanisms. FOXO3 protein, but not FOXO1 protein, appears to be a tumor suppressor that inhibits breast cancer by altering DNA damage response (DDR), thereby inducing p53-dependent apoptosis. This antitumor effect appears to be suppressed by excessive activity of the PI3K/AKT/mTOR pathway. High FOXO3 protein expression could be a biomarker of deficient DDR in breast tumors.

Ovarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. The majority are carcinomas, originating from epithelial cells that are in constant division and subjected to cyclical variations of the estrogen stimulus during the female hormonal cycle, therefore being vulnerable to DNA damage. A portion of breast and ovarian carcinomas arises in the context of DNA repair defects, in which genetic instability is the backdrop for cancer initiation and progression. For these tumors, DNA repair deficiency is now increasingly recognized as a target for therapeutics. In hereditary breast/ovarian cancers (HBOC), tumors with BRCA1/2 mutations present an impairment of DNA repair by homologous recombination (HR). For many years, BRCA1/2 mutations were only screened on germline DNA, but now they are also searched at the tumor level to personalize treatment. The reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of a HR-deficient signature. Evidence indicates that identifying the mechanism of HR inactivation should improve both genetic counseling and therapeutic response, since they can be useful as new biomarkers of response.

Background The WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α. Results To better understand the involvement of WWOX in breast tumorigenesis, we performed a yeast two-hybrid screen and co-immunoprecipitation assays to identify novel partners of this protein. We characterized the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) as a new regulator of WWOX. In breast cancer cells, VOPP1 sequestrates WWOX in lysosomes, impairs its ability to associate with p73α, and inhibits WWOX-dependent apoptosis. Overexpressed VOPP1 potentiates cellular transformation and enhances the growth of transplanted tumors in vivo. VOPP1 is overexpressed in breast tumors, especially in tumors that retain WWOX. Moreover, increased expression of VOPP1 is associated with reduced survival of patients with WWOX-positive, but not with WWOX-negative, tumors. Conclusions These findings emphasize the importance of the sequestration of WWOX by VOPP1 in addition to WWOX loss in breast tumors and define VOPP1 as a novel oncogene promoting breast carcinogenesis by inhibiting the anti-tumoral effect of WWOX. Electronic supplementary material The online version of this article (10.1186/s12915-018-0576-6) contains supplementary material, which is available to authorized users.

To ensure their high proliferation rate, tumor cells have an iron metabolic disorder causing them to have increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple-negative tumors, which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this study, we demonstrated that deferasirox (DFX) synergises with standard chemotherapeutic agents such as doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple-negative breast cancer (TNBC) cells. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient-derived xenografts without increasing the side-effects of chemotherapies alone or altering the global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve downregulation of the phosphoinositide 3-kinase and nuclear factor-κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Numerous studies have evaluated changes in time of testicular development in birds by exploratory laparotomy or post-mortem autopsy. The invasive nature of these approaches has obviously limited the frequency at which these measures can be collected. We demonstrate here that accurate assessment of gonadal size can be reliably and repeatedly obtained by computer-assisted X-ray tomography (CT scans). This approach provides images of the testes in the three orthogonal planes that allow measuring either the largest diameter or even the volume of the testes, providing results that match those obtained by surgical approaches.

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for patients with EGFR-positive tumors, this strategy of addressing cancer tumors by targeting EGFR with monoclonal antibodies is less-developed for patient diagnostic and monitoring. Indeed, antibodies exhibit a slow blood clearance, which is detrimental for positron emission tomography (PET) imaging. New molecular probes are proposed to overcome such limitations for patient monitoring, making use of low-molecular-weight protein scaffolds as alternatives to antibodies, such as Nanofitins with better pharmacokinetic profiles. Anti-EGFR Nanofitin B10 was reformatted by genetic engineering to exhibit a unique cysteine moiety at its C-terminus, which allows the development of a fast and site-specific radiolabeling procedure with 18F–4-fluorobenzamido-N-ethylamino-maleimide (18F–FBEM). The in vivo tumor targeting and i...

Background: RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). Methods: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT–PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT–PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/β-catenin pathway, was examined on the growth of an RSPO2-positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC. Results: We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO, and amplification or hypomethylation of RSPO genes. Patients with RSPO2-overexpressing tumours have a poorer metastasis-free survival (P=3.6 × 10−4). RSPO2 and RSPO4 stimulate Wnt/β-catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2-overexpressing PDX. Conclusions: RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.

The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.

Promoter mutations of pleckstrin homology domain-containing S1 (PLEKHS1) are frequent in several cancer types. To evaluate the DNA mutations, the mRNA expression and prognostic value of PLEKHS1 was evaluated in bladder cancer. We investigated DNA mutations and mRNA expression of PLEKHS1 in a first series of 154 bladder tumors [71 non-muscle-invasive bladder cancer (NMIBC) and 83 muscle-invasive bladder cancers (MIBC)] from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2006, and 20 normal bladder samples. Results were then validated in a second series of 181 bladder tumors (91 NMIBC and 90 MIBC). All patients have signed an informed consent form. DNA mutations were analysed by high-resolution melt analysis and sanger sequencing. The mRNA expression was measured by real-time reverse-transcriptase quantitative PCR. The results of the molecular analysis were compared with survival data. PLEKHS1 mutations occurred in 25.0 and 32.2% of NMIBC and MIBC, respectively in the first series. These results were confirmed in the second series (33.0 and 37.8% of NMIBC and MIBC, respectively). In MIBC, DNA mutations were significantly more frequent with the basal than non-basal phenotype (61.5 vs. 27.1%; P=0.0025). The PLEKHS1 mRNA level was increased in 22.5 and 27.7% of NMIBC and MIBC tumors but was not associated with DNA mutations. In NMIBC, PLEKHS1 mRNA overexpression was significantly associated with progression to muscle-invasive disease (P=0.0069) and remained an independent prognostic factor on multivariate analysis (P=0.034). DNA mutations of PLEKHS1 occurred in one-third of bladder tumors and was frequent in the basal MIBC phenotype. PLEKHS1 mRNA overexpression may be an independent prognostic factor of progression-free survival in NMIBC.

The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific.

Background: The Arp2/3 complex is required for cell migration and invasion. The Arp2/3 complex and its activators, such as the WAVE complex, are deregulated in diverse cancers. Here we investigate the expression of Arpin, the Arp2/3 inhibitory protein that antagonises the WAVE complex. Methods: We used qRT–PCR and reverse phase protein arrays in a patient cohort with known clinical parameters and outcome, immunofluorescence in breast biopsy cryosections and breast cancer cell lines. Results: Arpin was downregulated at the mRNA and protein levels in mammary carcinoma cells. Arpin mRNA downregulation was associated with poor metastasis-free survival (MFS) on univariate analysis (P=0.022). High expression of the NCKAP1 gene that encodes a WAVE complex subunit was also associated with poor MFS on univariate analysis (P=0.0037) and was mutually exclusive with Arpin low. Arpin low or NCKAP1 high was an independent prognosis factor on multivariate analysis (P=0.0012) and was strongly associated with poor MFS (P=0.000064). Conclusions: Loss of the Arp2/3 inhibitory protein Arpin produces a similar poor outcome in breast cancer as high expression of the NCKAP1 subunit of the Arp2/3 activatory WAVE complex.

Viticulture is of high socio-economic importance; however, its prevalent practices severely impact the environment and human health, and criticisms from society are raising. Vine managements systems are further challenged by climatic changes. Of the 8 million hectares grown worldwide, conventional and organic practices cover 90% and 9% of acreage, respectively. Biodynamic cultivation accounts for 1%. Although economic success combined with low environmental impact is widely claimed by biodynamic winegrowers from California, to South Africa, and France, this practice is still controversial in viticulture and scientific communities. To rethink the situation, we encouraged stakeholders to confront conventional and biodynamic paradigms in a Participative-Action-Research. Co-designed questions were followed up by holistic comparison of conventional and biodynamic vineyard managements. Here we show that the amplitude of plant responses to climatic threats was higher in biodynamic than conventional management. The same stood true for seasonal trends and pathogens attacks. This was associated with higher expression of silencing and immunity genes, and higher anti-oxidative and anti-fungal secondary metabolite levels. This suggests that sustainability of biodynamic practices probably relies on fine molecular regulations. Such knowledge should contribute to resolving disagreements between stakeholders and help designing the awaited sustainable viticulture at large.

Alternatively activated Mφs (AAMφ) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mφ responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor α-chain (IL-4Rα)-signalling in the dynamics of liver Mφ responses. We observed that IL-4Rα signalling was dispensable for the recruitment of Ly6Chi monocytes and for their conversion into F4/80hi CD64hi CD11bhi Mφ. Moreover, while IL-4Rα provided an AAMφ phenotype to liver F4/80hi CD64hi CD11bhi Mφ that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80hi CD64hi CD11blo Mφ did not upregulate the AAMφ signature gene Ym1. Rather, resident Mφ nearly disappeared by week 8 after infection and artificial ablation of resident Mφ in CD169DTR mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169+ cells in naive mice resulted in the accumulation of F4/80hi CD64hi CD11bhi Mφ, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80hi CD64hi CD11bhi Mφ with lyz2-dependent IL-4Rα contributing to the regulation of granuloma inflammation but being dispensable for host survival.

Increasing epidemiological and animal experimental data provide substantial support for the role of aryl hydrocarbon receptor (AhR) in mammary tumorigenesis. The effects of AhR have been clearly demonstrated in rodent models of breast carcinogenesis and in several established human breast cancer cell lines following exposure to AhR ligands or AhR overexpression. However, relatively little is known about the role of AhR in human breast cancers. AhR has always been considered to be a regulator of toxic and carcinogenic responses to environmental contaminants such as TCDD (dioxin) and benzo[a]pyrene (BaP). The aim of this study was to identify the type of breast tumors (ERα-positive or ERα-negative) that express AHR and how AhR affects human tumorigenesis. The levels of AHR, AHR nuclear translocator (ARNT) and AHR repressor (AHRR) mRNA expression were analyzed in a cohort of 439 breast tumors, demonstrating a weak association between high AHR expression and age greater than fifty years and ERα-negative status, and HR-/ERBB2 breast cancer subtypes. AHRR mRNA expression was associated with metastasis-free survival, while AHR mRNA expression was not. Immunohistochemistry revealed the presence of AhR protein in both tumor cells (nucleus and/or cytoplasm) and the tumor microenvironment (including endothelial cells and lymphocytes). High AHR expression was correlated with high expression of several genes involved in signaling pathways related to inflammation (IL1B, IL6, TNF, IL8 and CXCR4), metabolism (IDO1 and TDO2 from the kynurenine pathway), invasion (MMP1, MMP2 and PLAU), and IGF signaling (IGF2R, IGF1R and TGFB1). Two well-known ligands for AHR (TCDD and BaP) induced mRNA expression of IL1B and IL6 in an ERα-negative breast tumor cell line. The breast cancer ER status likely influences AhR activity involved in these signaling pathways. The mechanisms involved in AhR activation and target gene expression in breast cancers are also discussed.

// Francois Lallemand 1, * , Ambre Petitalot 1, 2, * , Sophie Vacher 1 , Leanne de Koning 3 , Karim Taouis 1 , Bernard S. Lopez 4 , Sophie Zinn-Justin 5 , Nicole Dalla-Venezia 6 , Walid Chemlali 1 , Anne Schnitzler 1 , Rosette Lidereau 1 , Ivan Bieche 1, 7, * and Sandrine M. Caputo 2, * 1 Service de genetique, unite de pharmacogenomique, Institut Curie, Paris, France 2 Service de genetique, unite de genetique constitutionnelle, Institut Curie, Paris, France 3 Departement de transfert, Institut Curie, Paris, France 4 CNRS UMR 8200, Gustave Roussy Cancer Institute, Universite Paris-Saclay, equipe labelisee par la Ligue contre le cancer, Villejuif, France 5 Laboratoire de biologie structurale et radiobiologie, IBITEC-S (CEA) and I2BC (UMR 9198, CEA, CNRS, Univ. Paris South), Gif-sur-Yvette, France 6 Centre de Recherche en Cancerologie de Lyon (CRCL)/INSERM U1052-CNRS UMR5286, Lyon, France 7 EA7331, Universite Paris Descartes, Paris, France * These authors contributed equally to this work Correspondence to: Sandrine M. Caputo, email: sandrine.caputo@curie.fr Keywords: gynecological cancers; cervical squamous cell carcinoma; endometrial adenocarcinoma; uc.189; prognosis Received: May 12, 2017 Accepted: December 22, 2017 Published: December 30, 2017 ABSTRACT In mammals, FOXO transcriptional factors form a family of four members (FOXO1, 3, 4, and 6) involved in the modulation proliferation, apoptosis, and carcinogenesis. The role of the FOXO family in breast cancer remains poorly elucidated. According to the cellular context and the stage of the disease, FOXOs can have opposite effects on carcinogenesis. To study the role of FOXOs in breast carcinogenesis in more detail, we examined their expression in normal tissues, breast cell lines, and a large series of breast tumours of human origin. We found a very low physiological level of FOXO6 expression in normal adult tissues and high levels of expression in foetal brain. FOXO gene expressions fluctuate specifically in breast cancer cells compared to normal cells, suggesting that these genes may have different roles in breast carcinogenesis. For the first time, we have shown that, among the various FOXO genes, only FOXO6 was frequently highly overexpressed in breast cell lines and tumours. We also found that inhibition of the endogenous expression of FOXO6 by a specific siRNA inhibited the growth of the human breast cell lines MDA-MB-468 and HCC-38. FACS and Western blot analysis showed that inhibition of endogenous expression of FOXO6 induced accumulation of cells in G0/G1 phase of the cell cycle, but not apoptosis. These results tend to demonstrate that the overexpression of the human FOXO6 gene that we highlighted in the breast tumors stimulates breast carcinogenesis by activating breast cancer cell proliferation.

The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/β-catenin pathway by preventing the nuclear import of disheveled 2 (DVL2) in human breast cancer cells. Here, it is revealed that WWOX also interacts with the BCL9-2, a cofactor of the Wnt/β-catenin pathway, to enhance the activity of the β-catenin–TCF/LEF (T-cell factor/lymphoid enhancer factors family) transcription factor complexes. By using both a luciferase assay in MCF-7 cells and a Xenopus secondary axis induction assay, it was demonstrated that WWOX inhibits the BCL9-2 function in Wnt/β-catenin signaling. WWOX does not affect the BCL9-2–β-catenin association and colocalizes with BCL9-2 and β-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the β-catenin–TCF1 interaction. Further examination found that HDAC3 associates with BCL9-2, enhances the inhibitory effect of WWOX on BCL9-2 transcriptional activity, and promotes the WWOX–BCL9-2 interaction, independent of its deacetylase activity. However, WWOX does not influence the HDAC3–BCL9-2 interaction. Altogether, these results strongly indicate that nuclear WWOX interacts with BCL9-2 associated with β-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the β-catenin–TCF1 interaction. The promotion of the WWOX–BCL9-2 interaction by HDAC3, independent of its deacetylase activity, represents a new mechanism by which this HDAC inhibits transcription. Implications: The inhibition of the transcriptional activity of BCL9-2 by WWOX and HDAC3 constitutes a new molecular mechanism and provides new insight for a broad range of cancers. Mol Cancer Res; 13(5); 902–12. ©2015 AACR.

International audience; PurposeThe molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants.MethodsFour BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay.ResultsWe identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities.ConclusionIn this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.

International audience; Wine growing has a high economic value globally, and vineyards, with their centenarian grape varieties, are an integral part of our societies. Yet with the use of spraying to control pathogens and weeds, mainstream viticulture has become a big pesticide consumer. Criticism of this conventional type of viticulture and its environmental/health impacts is increasing strongly throughout society. Until now, mainstream 'top-down' scientific-technical developments have focused on breeding for new varieties and on designing new agronomic models. In parallel, organic and biodynamic practices have been developing alternatives. Either way, changes do not develop on the expected time scale. We posit that the diversity of actors concerned, from winegrowers to technical advisers, consumer associations, conservationists, elected representatives, citizens, and scientists, all contribute to the perpetuation of a constrained situation, through their differences in perspectives and practices, positions, knowledge, and reasoning. To untangle this situation, we brought together these dissenting actors. With a view to resolving the epistemological challenges, we then characterized four types of knowledge, along with the reasoning in play, and designed a tetrahedral model to legitimize and inter-relate them. This tetrahedron supported co-construction of a collective epistemology after a paradigm shift, in which the dissensus became a resource on numerous occasions. We then highlighted masked double-bind situations and went further, developing a seven-step Argonaut to conduct the project. New practices were designed, to do away with herbicides and develop ecological grassing. They were implemented on a large scale in vineyards, within a short time frame, while enhancing the value of a neighbouring nature reserve. Projects currently underway in Switzerland, Germany, and France suggest that differences in knowledge are enriching, and yet that the reasoning at play fit with our tetrahedron model. We thus show that dissenting actors can dissolve agronomic/economic/ecological dilemmas, while acting under uncertainty, and foster agroecology development.

Background. Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. Method. While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. Results. Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. Conclusion. Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.

Background: Epigenetic deregulation is considered as a new hallmark of cancer. The long non-coding RNA MALAT1 has been implicated in several cancers; however, its role in breast cancer is still little known. Methods: We used RT–PCR, in situ hybridisation, and RPPA methods to quantify (i) the full-length (FL) and an alternatively spliced variant (Δsv) of MALAT1, and (ii) a panel of transcripts and proteins involved in MALAT1 pathways, in a large series of breast tumours from patients with known clinical/pathological status and long-term outcome. Results: MALAT1 was overexpressed in 14% (63/446) of the breast tumours. MALAT1-overexpressed tumour epithelial cells showed marked diffuse nuclear signals and numerous huge nuclear speckles. Screening of the dbEST database led to the identification of Δsv-MALAT1, a major alternatively spliced MALAT1 transcript, with a very different expression pattern compared with FL-MALAT1. This alternative Δsv-MALAT1 transcript was mainly underexpressed (18.8%) in our breast tumour series. Multivariate analysis showed that alternative Δsv-MALAT1 transcript is an independent prognostic factor. Δsv-MALAT1 expression was associated with alterations of the pre-mRNAs alternative splicing machinery, and of the Drosha-DGCR8 complex required for non-coding RNA biogenesis. Alternative Δsv-MALAT1 transcript expression was associated to YAP protein status and with an activation of the PI3K-AKT pathway. Conclusions: Our results reveal a complex expression pattern of various MALAT1 transcript variants in breast tumours, and suggest that this pattern of expressions should be taken into account to evaluate MALAT1 as predictive biomarker and therapeutic target.

Fermitin family member 1 (FERMT1, Kindlin-1) is an epithelial-specific regulator of integrin functions and is associated with Kindler syndrome, a genetic disorder characterized by skin blistering, atrophy, and photosensitivity. However, the possible role of kindlin-1 in cancer remains unknown. Kindlin-1 expression was quantified in several human cancers using quantitative real-time polymerase chain reaction and published microarray datasets. The association between kindlin-1 expression and patient metastasis-free survival (N = 516) was assessed with Kaplan-Meier analyses. Effects of ectopic expression or silencing of kindlin-1 on cell signaling, migration, and invasion were assessed in human breast cancer cell lines using western blotting, immunofluorescence, wound healing assays, and invasion on Matrigel or type I collagen substrates. Breast tumor growth and lung metastasis were evaluated in 12-week-old female BALB/c mice (10 controls and six Kindlin-1-knockdown mice). All statistical tests were two-sided. Kindlin-1 expression was consistently higher in tumors than in normal tissues in various cancer types metastasizing to the lungs, including colon and bladder cancer. Kindlin-1 expression was associated with metastasis-free survival in both breast and lung adenocarcinoma (breast cancer: hazard ratio of lung metastasis = 2.55, 95% confidence intervals [CI] = 1.39 to 4.69, P = .001; lung cancer: hazard ratio of metastasis = 1.96, 95% CI = 1.25 to 3.07, P = .001). Overexpression of kindlin-1 induced changes indicating epithelial-mesenchymal transition and transforming growth factor beta (TGF beta) signaling, constitutive activation of cell motility, and invasion (number of migrating cells, Kindlin-1 cells vs control, mean = 164.66 vs 19.00, difference = 145.6, 95% CI = 79.1 to 212.2, P = .004; invasion rate, Kindlin-1-cells vs control = 9.65% vs 1.92%, difference = 7.73%, 95% CI = 4.75 to 10.70, P < .001). Finally, Kindlin-1 depletion in an orthotopic mouse model statistically significantly inhibited breast tumor growth (P < .001) and lung metastasis (P = .003). These results suggest a role for kindlin-1 in breast cancer lung metastasis and lung tumorigenesis and advance our understanding of kindlin-1 as a regulator of TGF beta signaling, offering new avenues for therapeutic intervention against cancer progression.

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ subsection of the Methods section. The accession code is SRP125477.

Ubiquitin-dependent degradation plays an important role in the negative regulation of TGF-beta signaling. Here, we identify Tiul1 (for TGIF interacting ubiquitin ligase 1), a novel E3 ubiquitin ligase that inhibits TGF-beta signaling by targeting both the activated receptor and Smad2 for degradation. Tiul1 associates constitutively with Smad7 and induces degradation of the activated type I receptor without affecting the expression levels of Smad7. Tiul1 can also interact with Smad2 and the nuclear corepressor TGIF upon activation of TGF-beta signaling. Like Smad7, the steady-state levels of TGIF are not affected by Tiul1, but the interaction of Tiul1 with TGIF allows this ubiquitin ligase to target Smad2 for degradation. Consistent with this, overexpression of Tiul1 suppressed TGF-beta-induced growth arrest and transcriptional responses. In addition, silencing of Tiul1 or TGIF genes by siRNA resulted in suppression of the TGF-beta-dependent degradation of Smad2 and an enhancement of TGF-beta-mediated gene expression. These results reveal a new role for TGIF as a component of a ubiquitin ligase complex that mediates the degradation of Smad2 in response to TGF-beta signaling.

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation and the loss of responsiveness to TGF-beta may contribute to the development of human cancers. In hepatocellular carcinomas, the potential role of TGF-beta signaling as a tumor suppressor pathway can be illustrated by the presence of mutations in genes encoding TGF-beta receptors or downstream components of this signaling such as Smad2. Although Smad2 is mutated in hepatocellular carcinomas, the alteration of TGF-beta signaling with respect to tumor progression remains to be established. Using the HepG2 hepatoma cells, we showed here that expression of Smad2.Q407R, a missense mutation found in human hepatocellular carcinoma, was less effective than expression of wild-type Smad2 in enhancing the ability of TGF-beta to induce transcription from the Mix.2 promoter. This effect was specifically associated with a decrease in the steady-state level of Smad2.Q407R, presumably because of an enhancement of its ubiquitination and degradation through the proteasome machinery. More importantly, we found that the unstability of Smad2.Q407R was reversed when this mutant undergoes homo-oligomerization with wild-type Smad2 or hetero-oligomerization with Smad3 within the cells. Therefore, our findings allowed us to propose a novel mechanism for suppression of the deleterious effect of a tumor-derived mutation of Smad2, which loss may lead to dysregulated cell proliferation during tumorigenesis.

The Smad proteins are key intracellular effectors of transforming growth factor-beta (TGF-beta) cytokines. The ability of Smads to modulate transcription results from a functional cooperativity with the coactivators p300/cAMP-response element-binding protein-binding protein (CBP), or the corepressors TGIF and Ski. The c-Jun N-terminal kinase (JNK) pathway, another downstream target activated by TGF-beta receptors, has also been suggested to inhibit TGF-beta signaling through interaction of c-Jun with Smad2 and Smad3. Here we show that c-Jun directly interacts with Ski to enhance the association of Ski with Smad2 in the basal state. Interestingly, TGF-beta signaling induces dissociation of c-Jun from Ski, thereby relieving active repression by c-Jun. Moreover, activation of JNK pathway suppressed the ability of TGF-beta to induce dissociation of c-Jun from ski. Thus, the formation of a c-Jun/Ski complex maintains the repressed state of Smad2-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling by the JNK cascade.

WWOX is a tumor suppressor gene spanning the fragile site FRA16D and targeted by loss of heterozygosity or homozygous deletion in several tumor types. Wwox protein consists of two N-terminal WW domains that mediate protein-protein interactions and a C-terminal short-chain Dehydrogenase/Reductase domain (SDR). The WW1 module acts as a versatile platform linking WWOX with numerous multiprotein complexes. Thus, Wwox suppressor activity relies on its binding capacities to various partners. Wwox has been shown to interact with known proto-oncogenes such as p73, deltaNp63, AP2γ, c-jun, Erbb4, c-Met, Runx2 and Dvl-2. At the cellular level, Wwox has been shown to be a pro-apoptotic protein that induces cell death by acting in both the nucleus and cytoplasm. More recently, emerging evidence also suggest an important role of WWOX in DNA damage response. By using a yeast two-hybrid system and co-immunoprecipitation assays, we characterized Vopp1 (Vesicular Over-expressed in cancer Pro-survival Protein 1) as a new molecular partner of the tumor suppressor Wwox. VOPP1 gene localizes at the frequently amplified 7p11.2 locus and is often co-amplified with EGFR. It is overexpressed in multiple malignancies such as glioblastoma, gastric, head and neck and lung cancers. In this study, we demonstrate that VOPP1 physically interacts with Wwox in breast cancer cells. Upon binding, Wwox is recruited to the Vopp1-containing lysosomal compartment. This recruitment inhibits Wwox-mediated apoptosis at least in part by preventing Wwox-p73 interaction. In addition, Vopp1 acts as an oncogene as shown by its capacity to potentiate cellular transformation. Moreover, in breast cancer clinical samples, VOPP1 overexpression was detected predominantly in tumors retaining Wwox expression. Vopp1 overexpression is associated to a reduced survival of breast cancer patients, especially patients with luminal B tumor types. Remarkably, the VOPP1/WWOX expression ratio showed a significantly worst prognosis outperforming either gene alone. These findings highlight the importance of Wwox compartimentation in addition to Wwox loss in human cancer pathogenesis and define Vopp1 as a novel negative regulator of Wwox whose overexpression induces breast carcinogenesis by affecting the tumor suppressive activity of Wwox. Citation Format: François Lallemand, Florian Bonin, Rosette Lidereau, Keltouma Driouch. Vopp1 physically interacts with Wwox and inhibits its apoptotic function in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4303. doi:10.1158/1538-7445.AM2017-4303